Hedgehog antagonists having zinc binding moieties

ABSTRACT

The present invention provides compounds which antagonize hedgehog signaling and inhibit HDAC activity. The compounds can be used in methods of treating proliferative diseases and disorders such as cancer.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/932,395, filed on Jul. 1, 2013, which is a continuation ofInternational Application No. PCT/US2012/020092, which designated theUnited States and was filed on Jan. 3, 2012, published in English, whichclaims the benefit of U.S. Provisional Application No. 61/429,350, filedon Jan. 3, 2011 and U.S. Provisional Application No. 61/564,549, filedon Nov. 29, 2011. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Hedgehog (Hh) protein was first identified in Drosophila melanogaster asa segment-polarity gene involved in embryo patterning (Nusslein-Voihardet al., Roux. Arch. Dev. Biol., 193: 267-282 (1984)). Three orthologs ofDrosophila hedgehog (Sonic, Desert and Indian) were later found to occurin all vertebrates, including fish, birds and mammals. Desert hedgehog(DHh) is expressed principally in the testes, both in mouse embryonicdevelopment and in the adult rodent and human; Indian hedgehog (IHh) isinvolved in bone development during embryogenesis and in bone formationin the adult; and, Sonic hedgehog (SHh) is expressed at high levels inthe notochord and floor plate of developing vertebrate embryos. In vitroexplant assays as well as ectopic expression of SHh in transgenicanimals have shown that SHh plays a key role in neuronal tube patterning(Echelard et al., Cell, 75:1417-1430 (1993); Ericson et al., Cell, 81:747-56 (1995); Marti et al., Nature, 375: 322-5 (1995); Krauss et al.,Cell, 75: 1432-44 (1993); Riddle et al., Cell, 75: 1401-16 (1993);Roelink et al., Cell, 81: 445-55 (1995); Hynes et al., Neuron, 19: 15-26(1997)). Hh also plays a role in the development of limbs (Krauss etal., Cell, 75: 143-144 (1993); Laufer et al., Cell, 79: 993-1003(1994)), somites (Fan and Tessier-Lavigne, Cell, 79: 1175-86 (1994);Johnson et al., Cell, 79: 1165-73 (1994)), lungs (Bellusci et al.,Develop., 124: 53-63 (1997) and skin (Oro et al., Science, 276: 817-21(1997)).

Likewise, IHh and DHh are involved in bone, gut and germinal celldevelopment (Apelqvist et al., Curr. Biol., 7: 80 1-4 (1997); Bellusciet al., Development, 124: 53-63 (1997); Bitgood et al., Curr. Biol., 6:298-304 (1996); Roberts et al., Development, 121: 3163-74 (1995)).

Human SHh is synthesized as a 45 kDa precursor protein which isautocatalytically cleaved to yield a 20 kDa N-terminal fragment that isresponsible for normal hedgehog signaling activity; and a 25 kDaC-terminal fragment that is responsible for autoprocessing activity inwhich the N-terminal fragment is conjugated to a cholesterol moiety(Lee, J. J., et al. (1994) Science, 266: 1528-1536; Bumcrot, D. A., etal. (1995), Mol. Cell Biol., 15: 2294-2303; Porter, J. A., et al. (1995)Nature, 374: 363-366). The N-terminal fragment consists of amino acidresidues 24-197 of the full-length precursor sequence which remainsmembrane-associated through the cholesterol at its C-terminus (Porter,J. A., et al. (1996) Science, 274: 255-258; Porter, J. A., et al. (1995)Cell, 86(2): 1-34). Cholesterol conjugation is responsible for thetissue localization of the hedgehog signal.

At the cell surface, the Hh signal is thought to be relayed by the 12transmembrane domain protein Patched (Ptc) (Hooper and Scott, Cell, 59:751-65 (1989); Nakano et al., Nature, 341: 508-13 (1989)) and theG-protein-coupled-like receptor Smoothened (Smo) (Alcedo et al., Cell,86(22): 1-232 (1996); van den Heuvel and Ingham, Nature, 382: 547-551(1996)). Both genetic and biochemical evidence support a receptor modelwhere Ptc and Smo are part of a multicomponent receptor complex (Chenand Struhl, Cell, 87: 553-63 (1996); Marigo et al., Nature, 384: 176-9(1996); Stone et al., Nature, 384: 129-34 (1996)). Upon binding of Hh toPtc, the normal inhibitory effect of Ptc on Smo is relieved, allowingSmo to transduce the Hh signal across the plasma membrane. However, theexact mechanism by which Ptc controls Smo activity has yet to beclarified.

The signaling cascade initiated by Smo results in activation of Glitranscription factors that translocate into the nucleus where theycontrol transcription of target genes. Gli has been shown to influencetranscription of Hh pathway inhibitors such as Ptc and Hip 1 in anegative feedback loop indicating that tight control of Hh pathwayactivity is required for proper cellular differentiation and organformation.

Hedgehog pathway signaling has been implicated in tumorigenesis whenreactivated in adult tissues through sporadic mutations or othermechanisms. Three mechanisms have been proposed for the Hedgehogpathway's involvement in cancer: Type 1 cancers are caused byloss-of-function mutations in Patched 1 (PTCH₁) or gain-of-functionmutations in Smoothened (SMOH) lead to constitutive Hedgehog (Hh)pathway activation. Type 2 cancers rely on an autocrine model in whichtumor cells themselves produce and respond to Hh ligand. Type 3 is aparacrine model in which tumor cells produce Hh ligand and surroundingstromal cells respond by producing additional growth factors to supporttumor growth or survival, for example, IGF (Insulin-Like Growth Factor)and VEGF (Vascular Endothelial Growth Factor) (Rubin, L. L. and deSauvage, F. J. Nature Rev. Drug Discovery, 5: 1026-1033 (2006)).

Dysfunctional Ptc gene mutations have also been associated with a largepercentage of sporadic basal cell carcinoma tumors (Chidambaram et al.,Cancer Research, 56: 4599-601 (1996); Gailani et al., Nature Genet., 14:78-81 (1996); Haim et al., Cell, 85: 841-51 (1996); Jolmson et al.,Science, 272: 1668-71 (1996); Unden et al., Cancer Res., 56: 4562-5;Wicking et al., Am. J. Hum. Genet., 60: 21-6 (1997)). Loss of Ptcfunction is thought to cause an uncontrolled Smo signaling in basal cellcarcinoma. Similarly, activating Smo mutations have been identified insporadic BCC tumors (Xie et al., Nature, 391: 90-2 (1998)), emphasizingthe role of Smo as the signaling subunit in the receptor complex forSHh.

The development of resistance to Shh pathway inhibitors has beenobserved in animal tumor models (Buonamici, S. et al., Science Trans.Med., 2010, 2: 51ra70; Osherovich, L. SciBX 2010, 3(40)) and in humans(Yauch, R. et al, Science, 2009). Several mechanisms for resistance wereidentified, including SMO mutations, Gli2 amplification and upregulationof the IGF-1R-PI3K signaling pathway.

Various inhibitors of hedgehog signaling have been investigated. Thefirst Hedgehog signaling inhibitor to be discovered was cyclopamine, anatural alkaloid that has been shown to arrest cell cycle at GO-Gl andto induce apoptosis in SCLC. A number of synthetic small moleculeHedgehog pathway inhibitors are currently under development (Trembley,M. R. et al., Expert Opin. Ther. Patents, 19(8):1039-56 (2009)). Despiteadvances with these and other compounds, there remains a need for potentinhibitors of the hedgehog signaling pathway.

Histone acetylation is a reversible modification, with deacetylationbeing catalyzed by a family of enzymes termed histone deacetylases(HDACs). HDAC's are represented by 18 genes in humans and are dividedinto four distinct classes (J. Mol Biol, 2004, 338(1): 17-31). Inmammalians class I HDAC's (HDAC1-3, and HDAC8) are related to yeast RPD3HDAC, class 2 HDAC's (HDAC4-7, HDAC9 and HDAC10) are related to yeastHDAC1, class 4 (HDAC11), and class 3 HDAC's (a distinct classencompassing the sirtuins) are related to yeast Sir2.

Csordas (Biochem. J., 1990, 286: 23-38) teaches that histones aresubject to post-translational acetylation of the ε-amino groups ofN-terminal lysine residues, a reaction that is catalyzed by histoneacetyl transferase (HAT1). Acetylation neutralizes the positive chargeof the lysine side chain, and is thought to impact chromatin structure.Indeed, access of transcription factors to chromatin templates isenhanced by histone hyperacetylation, and enrichment in underacetylatedhistone H4 has been found in transcriptionally silent regions of thegenome (Taunton et al., Science, 1996, 272:408-411). In the case oftumor suppressor genes, transcriptional silencing due to histonemodification can lead to oncogenic transformation and cancer.

Several classes of HDAC inhibitors currently are marketed or underevaluation in clinical trials. Examples include the hydroxamic acidderivatives suberoylanilide hydroxamic acid (SAHA) and Romidepsin, whichare marketed, and PXD101, LH-589 and LAQ824, which are currently inclinical development. In the benzamide class of HDAC inhibitors, MS-275,MGCD₀₁₀₃ and CI-994 are currently being investigated in clinical trials.Mourne et al. (Abstract #4725, AACR 2005), demonstrate that thiophenylmodification of benzamides significantly enhances HDAC inhibitoryactivity against HDAC1.

In addition, recent studies have shown that the acetylation of Gliproteins functions as a key transcriptional checkpoint of Hedgehogsignaling. It was found that an autoregulatory loop exists whereby Shhincreases HDAC1 levels and HDAC1 in turn enhances Hh-induced signalactivation by deacetylation of Gli1 and Gli2. Moreover, inhibitors ofclass 1 HDACs suppress Gli1 and Gli2 activation, thus suppressingHh-dependent growth of neural progenitors and tumor cells. (Canettieri,G. et al., Nature Cell Biology, 2010, 12: 132-142).

Certain cancers have been effectively treated with agents targetingmultiple signaling pathways. A recent study demonstrated that thecombined targeting of HDACs and Hh signaling enhanced cytotoxicity inpancreatic adenocarcinoma. (Chun, S. et al., Cancer Biol. & Therapy,2009, 8(14): 1328-1339). However, treatment regimes using a cocktail ofcytotoxic drugs often are limited by dose limiting toxicities anddrug-drug interactions. More recent advances with molecularly targeteddrugs have provided some new approaches to combination treatment forcancer, allowing multiple targeted agents to be used simultaneously, orcombining these new therapies with standard chemotherapeutics orradiation to improve outcome without reaching dose limiting toxicities.However, in many cases, dose-limiting toxicities are reached beforepharmacologically meaningful levels of exposure are achieved, and theability to use such combinations currently is limited to drugs that showcompatible pharmacokinetic and pharmacodynamic properties. In addition,the regulatory requirements to demonstrate safety and efficacy ofcombination therapies can be more costly and lengthy than correspondingsingle agent trials. Once approved, combination strategies may also beassociated with increased costs to patients, as well as decreasedpatient compliance.

SUMMARY OF THE INVENTION

The present invention relates to hedgehog antagonist compounds havingzinc-binding moieties and their use in the treatment of hedgehog andHDAC related diseases and disorders such as cancer and other diseasesand disorders characterized by uncontrolled cell proliferation. Thecompounds of the present invention act as HDAC inhibitors by virtue oftheir ability to bind zinc ions and as inhibitors of the Hedgehogsignaling pathway. Combining hedgehog antagonism and HDAC inhibitioninto a single molecule may provide a synergistic effect in therapeuticapplications, and in particular, to the treatment of cancer.

Accordingly, one aspect of the present invention provides a compound ofFormula (I) or Formula (II):

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof;wherein:Ring A is an aromatic, saturated or partially unsaturated carbocycle;preferably a monocyclic, bicyclic or polycyclic C₃-C₁₂-carbocycle;

-   E is substituted or unsubstituted aryl or substituted or    unsubstituted heteroaryl or substituted or unsubstituted saturated    or partially unsaturated heterocyclyl;-   L is substituted or unsubstituted aryl or substituted or    unsubstituted heteroaryl or substituted or unsubstituted saturated    or partially unsaturated heterocyclyl;-   Q is substituted or unsubstituted aryl; substituted or unsubstituted    heteroaryl or substituted or unsubstituted saturated or partially    unsaturated heterocyclyl;-   G is substituted or unsubstituted aryl, substituted or unsubstituted    heteroaryl or substituted or unsubstituted saturated or partially    unsaturated heterocyclyl;-   K is halogen, preferably Cl;-   X is absent, —O—, —N(R₂)—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,    —OC(O)—, —C(O)N(R₂)—, —N(R₂)C(O)—, —S(O)₂N(R₂)—, or —N(R₂)S(O)₂—;-   R₂ is hydrogen or aliphatic, preferably hydrogen or C₁-C₆-alkyl, and    more preferably hydrogen or methyl;-   n is 0 or 1;-   B is a bond or a linker; and-   D is selected from:    -   (a)

-   -   where W is O or S; J is O, NH or NCH₃; and R₃₁ is hydrogen or        lower alkyl;    -   (b)

-   -   where W is O or S; Y₂ is absent, N, or CH; Z is N or CH; R₃₂ and        R₃₄ are independently hydrogen, OR′, aliphatic group, provided        that if R₃₂ and R₃₄ are both present, one of R₃₂ or R₃₄ must be        OR′ and if Y₂ is absent, R₃₄ must be OR′; R₃₃ is hydrogen or        aliphatic group; and R′ is hydrogen, aliphatic or acyl,        preferably hydrogen; preferably Y₂ and R₃₂ are absent, Z is N,        R₃₄ is hydroxy and R₃₃ is hydrogen;    -   (c)

-   -   where W is O or S; Y₁ and Z₁ are independently N, C or CH; and    -   (d)

-   -   where Z, Y₂, and W are as previously defined; R₁₁ and R₁₂ are        independently selected from hydrogen or aliphatic; R₂₁, R₂₂ and        R₂₃ are independently selected from hydrogen, hydroxy, amino,        halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,        sulfonyl, acyl, aliphatic, substituted aliphatic, aryl,        substituted aryl, heteroaryl, substituted heteroaryl,        heterocyclic, and substituted heterocyclic.

Another aspect of the invention provides methods of inhibiting hedgehogsignaling activity in a cell, by contacting the cell with an effectivehedgehog inhibitory amount of a compound of Formula I or Formula II, ora stereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof.

Another aspect of the invention provides methods of inhibiting HDACactivity in a cell, by contacting the cell with an effective HDACinhibitory amount of a compound of Formula I or Formula II, or astereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds which arerepresented by Formula III or Formula IV:

where Ring A, K, G, Q, X, B, D, L and E have the meanings given above.

In another embodiment, the compounds of the invention are represented byFormula V or VI:

and stereoisomers, geometric isomers, tautomers, pharmaceuticallyacceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and Dhave the meanings given above.

In an embodiment, the compounds of the invention are represented byFormula VII or VIII:

and stereoisomers, geometric isomers, tautomers, pharmaceuticallyacceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and Dhave the meanings given above. Preferably, G and L are eachindependently substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, and more preferably G and L are eachindependently substituted or unsubstituted phenyl or substituted orunsubstituted pyridyl. Preferably, E and Q are each independentlysubstituted or unsubstituted heteroaryl.

In an embodiment, the compounds of the invention are represented byFormula IX or X:

and stereoisomers, geometric isomers, tautomers, pharmaceuticallyacceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and Dhave the meanings given above. Preferably, G and L are eachindependently heterocyclyl, preferably heterocycloalkyl.

In one embodiment, the present invention provides compounds which arerepresented by Formula XI:

and stereoisomers, geometric isomers, tautomers, pharmaceuticallyacceptable salts and prodrugs thereof;wherein:one of W₁-W₅ is C(X—B-D) and the others are each independently N or CR₃,provided that no more than three of W₁-W₅ are N;each R₃ is independently selected from hydrogen, hydroxy, amino,halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl,aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; andX, B and D have the meanings given for these variables above.

In preferred embodiments of the compounds of Formula XI, E issubstituted or unsubstituted pyridyl, such as substituted orunsubstituted pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, or substituted orunsubstituted benzimidazolyl, such as substituted or unsubstitutedbenzimidazol-2-yl. In particularly preferred embodiments, E is selectedfrom the groups set forth below:

In another preferred embodiment of the compounds of Formula XI, thegroup

is selected from the groups shown below:

In another embodiment, the present invention provides compounds whichare represented by Formula XII:

and stereoisomers, geometric isomers, tautomers, pharmaceuticallyacceptable salts and prodrugs thereof;wherein:X₁-X₅ are each independently selected from N and CR₃, provided that atleast two of X₁-X₅ are CR₃; andQ, D, B, X and R₃ have the meanings given for these variables above.

In preferred embodiments of the compounds of Formula XII, Q issubstituted or unsubstituted pyridyl, substituted or unsubstitutedpyrimidyl or substituted or unsubstituted benzimidazolyl. Inparticularly preferred embodiments, Q is selected from the groups below,

wherein the bond to the benzene ring is denoted by

, and the bond to X is denoted by

.

In other preferred embodiments of the compounds of Formula XII, thegroup

is substituted or unsubstituted phenyl, substituted or unsubstitutedpyridyl, such as substituted or unsubstituted pyrid-2-yl, pyrid-3-yl orpyrid-4-yl, or substituted or unsubstituted pyrimidyl, such aspyrimid-2-yl, pyrimid-4-yl or pyrimid-5-yl. In particularly preferredembodiments, this group is selected from those set forth below:

In a preferred embodiment, the bivalent B is a direct bond or straight-or branched-, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl,heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl,alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl,alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl,alkenylheteroarylalkyl, alkenylheteroarylalkenyl,alkenylheteroarylalkynyl, alkynylheteroarylalkyl,alkynylheteroarylalkenyl, alkynylheteroarylalkynyl,alkylheterocyclylalkyl, alkylheterocyclylalkenyl,alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl,alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl,alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl,alkylheteroaryl, alkenylheteroaryl, or alkynylheteroaryl, in whichgroups one or more methylenes can be interrupted or terminated by O, S,S(O), SO₂, N(R₂), C(O), substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, or substituted or unsubstitutedheterocyclic; such divalent B linkers include but are not limited toalkyl, alkenyl, alkynyl, alkylaryl, alkenylaryl, alkynylaryl,alkylheterocyclylaryl, alkylheterocyclylarylalkyl,alkylheterocyclylheteroaryl, alkylheterocyclylheteroarylalkyl,alkoxyaryl, alkylaminoaryl, alkoxyalkyl, alkylaminoalkyl,alkylheterocycloalkyl, alkylheteroarylalkyl, alkylamino, aryl,heteroaryl, heterocyclyl, N(R₂)alkenyl, N(R₂)alkynyl, N(R₂)alkoxyalkyl,N(R₂)alkylaminoalkyl, N(R₂)alkylaminocarbonyl, N(R₂)alkylaryl,N(R₂)alkenylaryl, N(R₂)alkynylaryl, N(R₂)alkoxyaryl,N(R₂)alkylaminoaryl, N(R₂)cycloalkyl, N(R₂)aryl, N(R₂)heteroaryl,N(R₂)heterocycloalkyl, N(R₂)alkylheterocycloalkyl, alkoxy, O-alkenyl,O-alkynyl, O-alkoxyalkyl, O-alkylaminoalkyl, O-alkylaminocarbonyl,O-alkylaryl, O-alkenylaryl, O-alkynylaryl, O-alkoxyaryl,O-alkylaminoaryl, O-cycloalkyl, O-aryl, O-heteroaryl,O-heterocycloalkyl, O-alkylheterocycloalkyl, C(O)alkyl, C(O)-alkenyl,C(O)alkynyl, C(O)alkylaryl, C(O)alkenylaryl, C(O)alkynylaryl,C(O)alkoxyalkyl, C(O)alkylaminoalkyl, C(O)alkylaminocarbonyl,C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CON(R₂),CON(R₂)alkyl, CON(R₂)alkenyl, CON(R₂)alkynyl, CON(R₂)alkylaryl,CON(R₂)alkenylaryl, CON(R₂)alkynylaryl, CON(R₂)alkoxyalkyl,CON(R₂)alkylaminoalkyl, CON(R₂)alkylaminocarbonyl, CON(R₂)alkoxyaryl,CON(R₂)alkylaminoaryl, CON(R₂)cycloalkyl, CON(R₂)aryl,CON(R₂)heteroaryl, CON(R₂)heterocycloalkyl,CON(R₂)alkylheterocycloalkyl, N(R₂)C(O)alkyl, N(R₂)C(O)alkenyl,N(R₂)C(O)— alkynyl, N(R₂)C(O)alkylaryl, N(R₂)C(O)alkenylaryl,N(R₂)C(O)alkynylaryl, N(R₂)C(O)alkoxyalkyl, N(R₂)C(O)alkylaminoalkyl,N(R₂)C(O)alkylaminocarbonyl, N(R₂)C(O)alkoxyaryl,N(R₂)C(O)alkylaminoaryl, N(R₂)C(O)cycloalkyl, N(R₂)C(O)aryl,N(R₂)C(O)heteroaryl, N(R₂)C(O)heterocycloalkyl,N(R₂)C(O)alkylheterocycloalkyl, NHC(O)NH, NHC(O)NH-alkyl,NHC(O)NH-alkenyl, NHC(O)NH-alkynyl, NHC(O)NH-alkylaryl,NHC(O)NH-alkenylaryl, NHC(O)NH-alkynylaryl, NHC(O)NH-alkoxyaryl,NHC(O)NH-alkylaminoaryl, NHC(O)NH-cycloalkyl, NHC(O)NH-aryl,NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl,NHC(O)NH-alkylheterocycloalkyl, S-alkyl, S-alkenyl, S-alkynyl,S-alkoxyalkyl, S-alkylaminoalkyl, S-alkylaryl, S-alkylaminocarbonyl,S-alkylaryl, S-alkynylaryl, S-alkoxyaryl, S-alkylaminoaryl,S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl,S-alkylheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl,S(O)alkoxyalkyl, S(O)alkylaminoalkyl, S(O)alkylaminocarbonyl,S(O)alkylaryl, S(O)alkenylaryl, S(O)alkynylaryl, S(O)alkoxyaryl,S(O)alkylaminoaryl, S(O)cycloalkyl, S(O)aryl, S(O)heteroaryl,S(O)heterocycloalkyl, S(O)alkylheterocycloalkyl, S(O)₂alkyl,S(O)₂alkenyl, S(O)₂alkynyl, S(O)₂alkoxyalkyl, S(O)₂alkylaminoalkyl,S(O)₂alkylaminocarbonyl, S(O)₂alkylaryl, S(O)₂alkenylaryl,S(O)₂alkynylaryl, S(O)₂alkoxyaryl, S(O)₂alkylaminoaryl, S(O)₂cycloalkyl,S(O)₂aryl, S(O)₂heteroaryl, S(O)₂heterocycloalkyl,S(O)₂alkylheterocycloalkyl, S(O)₂heterocyclylalkyl,S(O)₂heterocyclylalkenyl, S(O)₂heterocyclylalkynyl, SO₂NH, SO₂NH-alkyl,SO₂NH-alkenyl, SO₂NH-alkynyl, SO₂NH-alkylaryl, SO₂NH-alkenylaryl,SO₂NH-alkynylaryl, SO₂NH-cycloalkyl, SO₂NH-aryl, SO₂NH-heteroaryl,SO₂NH-heterocycloalkyl, SO₂NH-alkylheterocycloalkyl, alkylaryloxyalkoxy,alkylaryloxyalkylamino, alkylarylaminoalkoxy, alkylarylaminoalkylamino,alkylarylalkylaminoalkoxy, alkylarylalkylaminoalkoxy,alkenylaryloxyalkoxy, alkenylaryloxyalkylamino, alkenylarylaminoalkoxy,alkenylarylaminoalkylamino, alkenylarylalkylaminoalkoxy,alkenylarylalkylaminoalkylamino.

In a more preferred embodiment, B is a straight chain alkyl, alkenyl,alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl,heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl,alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl,alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl,alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl,alkenylheteroarylalkenyl, alkenylheteroarylalkynyl,alkynylheteroarylalkyl, alkynylheteroarylalkenyl,alkynylheteroarylalkynyl, alkylheterocyclylalkyl,alkylheterocyclylalkenyl, alkylhererocyclylalkynyl,alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl,alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl,alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, oralkynylhereroaryl. In these linkers, one or more methylenes can beinterrupted or terminated by —O—, —N(R₂)—, —C(O)—, —C(O)N(R₂)—, or—C(O)O—.

In one embodiment, the linker B is between 1-24 carbon atoms, preferably4-24 carbon atoms, preferably 4-18 carbon atoms, more preferably 4-12carbon atoms, and most preferably about 4-10 carbon atoms.

In a preferred embodiment, B is selected from straight chain C₁-C₁₀alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, alkylamino, alkoxyC₁-C₁₀alkylamino,alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀alkenyl,heteroarylC₂-C₁₀alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl,heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀alkynyl,heteroaryloxyC₁-C₁₀alkylamino, heteroaryloxyC₁-C₁₀alkoxy. In the mostpreferred embodiments, the D group is attached to B via an aliphaticmoiety carbon chain, an aryl group or a heteroaryl group within B.

In another preferred embodiment, B is a direct bond, aryl, heteroaryl,C₂-C₁₀-alkyl, C₂-C₁₀-alkenyl, aryl-C₂-C₁₀-alkyl, aryl-C₂-C₁₀-alkenyl,aryloxy-C₁-C₁₀-alkyl, heterocyclylheteroaryl,C₁-C₁₀-alkylheterocyclylheteroaryl, or C₁-C₁₀-alkylaminoheteroaryl.

It is understood that alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl and the like can be further substituted.

In certain embodiments, the compounds of Formulas I and II arerepresented by Formulas XIII and XIV, respectively:

wherein M₁ is absent, O, S, NR₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, heteroaryl, heterocyclic, SO, SO₂ or C═O; M₂ is absent,C₁-C₆ alkyl, O, NR₂-heterocyclic, aryl, heteroaryl, or C═O; M₃ isabsent, O, NR₂, S, SO, SO₂, CO, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, heteroaryl, or heterocyclic; M₄ is absent, O, NR₂,heteroaryl, heterocyclic or aryl; and M₅ is absent, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₅alkynyl, heteroaryl, heterocyclic or aryl; and E, L, Q, G,Z, Y₂, R₃₂, R₃₃ and R₃₄ have the definitions given for these variablesabove. Preferably, Y₂ and R₃₂ are absent, Z is N, R₃₃ is H and R₃₄ ishydroxy.

Specific compounds of the invention are set forth in the Table below.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

249

250

251

252

253

254

255

264

265

266

267

The invention further provides methods for the prevention or treatmentof hedgehog-related diseases or disorders, and in particular, diseasesor disorders involving aberrant proliferation, differentiation orsurvival of cells. In one embodiment, the invention further provides forthe use of one or more compounds of the invention in the manufacture ofa medicament for halting or decreasing diseases involving aberrantproliferation, differentiation, or survival of cells. In preferredembodiments, the disease is cancer. In one embodiment, the inventionrelates to a method of treating cancer in a subject in need of treatmentcomprising administering to said subject a therapeutically effectiveamount of a compound of the invention. In another embodiment, theinvention further provides methods for the prevention or treatment ofnon-cancer hedgehog-related diseases or disorders, such as psoriasis.The compounds of the invention can also be used to treat diseases ordisorders associated with aberrant or uncontrolled angiogenesis,including macular degeneration, diabetic retinopathy, retinopathy ofprematurity, rheumatoid arthritis and obesity. In addition, compounds ofthe invention may be used to down-regulate hair growth.

By virtue of the dual HDAC and Hedgehog inhibitory activities of thecompounds of the present invention, the invention further provides amethod for treating certain cancers which are resistant to the action ofHedgehog pathway signaling inhibitors alone. Such resistance may becharacterized by one or more mutations in proteins involved in theHedgehog signaling cascade above the level of Gli transcriptionactivation. The present compounds having HDAC inhibiting activity maynonetheless be useful for treating cancers having increased hedgehoglevels by inhibiting the deacetylation of the Gli1 and Gli2transcription activators.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

In preferred embodiments, the cancer is associated with aberranthedgehog signaling, for example, when Patched fails to, or inadequately,represses Smoothened (Ptc loss of function phenotype) and/or whenSmoothened is active regardless of Patched repression (Smo gain-offunction phenotype) and/or when the Hedgehog ligand is upregulatedregardless of patched or smoothened mutational status. Examples of suchcancer types include basal cell carcinoma, neuroectodermal tumors, suchas medulloblastoma, meningioma, hemangioma, glioblastoma, pancreaticadenocarcinoma, squamous lung carcinoma, small cell lung cancer,non-small cell lung cancer, ovarian cancer, prostate cancer, livercancer, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, esophagealcancer, stomach cancer, biliary tract cancer, renal carcinoma andthyroid carcinoma. Furthermore, compounds of the invention may be usefulin the treatment of hematologic tumors such as leukemias, lymphomas andmyelomas as listed above.

Additional cancers that the compounds described herein may be useful intreating are, for example, colon carcinoma, familiary adenomatouspolyposis carcinoma and hereditary non-polyposis colorectal cancer, ormelanoma. Further, cancers include, but are not limited to, labialcarcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma,salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroidcancer (medullary and papillary thyroid carcinoma), renal carcinoma,kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma,endometrium carcinoma, chorion carcinoma, testis carcinoma, urinarycarcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma,meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma,teratoma, retinoblastoma, choroidea melanoma, seminoma,rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma,myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

In one aspect of the invention, the present invention provides for theuse of one or more compounds of the invention in the manufacture of amedicament for the treatment of cancer.

In one embodiment, the present invention includes the use of one or morecompounds of the invention in the manufacture of a medicament thatprevents further aberrant proliferation, differentiation, or survival ofcells. For example, compounds of the invention may be useful inpreventing tumors from increasing in size or from reaching a metastaticstate. The subject compounds may be administered to halt the progressionor advancement of cancer or to induce tumor apoptosis or to inhibittumor angiogenesis. In addition, the instant invention includes use ofthe subject compounds to prevent a recurrence of cancer.

This invention further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

“Combination therapy” includes the administration of the subjectcompounds in further combination with other biologically activeingredients (such as, but not limited to, a second and differentantineoplastic agent) and non-drug therapies (such as, but not limitedto, surgery or radiation treatment). For instance, the compounds of theinvention can be used in combination with other pharmaceutically activecompounds, preferably compounds that are able to enhance the effect ofthe compounds of the invention. The compounds of the invention can beadministered simultaneously (as a single preparation or separatepreparation) or sequentially to the other drug therapy. In general, acombination therapy envisions administration of two or more drugs duringa single cycle or course of therapy.

In one aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate protein kinases involved in various disease states or targetsdownstream thereof. Examples of such kinases may include, but are notlimited to: serine/threonine specific kinases, receptor tyrosinespecific kinases and non-receptor tyrosine specific kinases.Serine/threonine kinases include mitogen activated protein kinases(MAPK), meiosis specific kinase (MEK), RAF and aurora kinase. Examplesof receptor kinase families include epidermal growth factor receptor(EGFR) (e.g., HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, Xmrk,DER, Let23); fibroblast growth factor (FGF) receptor (e.g., FGF-R1,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocytegrowth/scatter factor receptor (HGFR) (e.g., MET, RON, SEA, SEX);insulin receptor (e.g., IGFI-R, PI3K, AKT, mTor); Eph (e.g., CEKS, CEK8,EBK, ECK, EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl(e.g., Mer/Nyk, Rse); RET; and platelet-derived growth factor receptor(PDGFR) (e.g., PDGFα-R, PDGβ-R, CSF1-R/FMS, SCF-R/C-KIT, VEGF-R/FLT,NEK/FLK1, FLT3/FLK2/STK-1). Non-receptor tyrosine kinase familiesinclude, but are not limited to, BCR-ABL (e.g., p43^(ab1), ARG); BTK(e.g., ITK/EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate non-kinase biological targets or processes. Such targetsinclude histone deacetylases (HDAC), DNA methyltransferase (DNMT), heatshock proteins (e.g., HSP90), and proteosomes.

In a preferred embodiment, subject compounds may be combined withantineoplastic agents (e.g., small molecules, monoclonal antibodies,antisense RNA, and fusion proteins) that inhibit one or more biologicaltargets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent,Sprycel, Nexavar, CNF2024, RG108, BMS387032, Affinitak, Avastin,Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322, Obatodax,ABT737 and AEE788. Such combinations may enhance therapeutic efficacyover efficacy achieved by any of the agents alone and may prevent ordelay the appearance of resistant mutational variants. For example, thesubject compounds may advantageously be used in combination with aBCL-ABL inhibitor such as Sprycel for the treatment of hematologictumors such as leukemias, lymphomas and myelomas.

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents encompass a wide range of therapeutic treatmentsin the field of oncology. These agents are administered at variousstages of the disease for the purposes of shrinking tumors, destroyingremaining cancer cells left over after surgery, inducing remission,maintaining remission and/or alleviating symptoms relating to the canceror its treatment. Examples of such agents include, but are not limitedto, alkylating agents such as mustard gas derivatives (Mechlorethamine,cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines(thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazinesand Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide),Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide andmetal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloidssuch as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxeland Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine andVinorelbine), and Camptothecan analogs (Irinotecan and Topotecan);anti-tumor antibiotics such as Chromomycins (Dactinomycin andPlicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibioticssuch as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such asfolic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed,Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists(6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine,Nelarabine and Pentostatin); topoisomerase inhibitors such astopoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase IIinhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide);monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab,Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor(Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubuleagents (Estramustine); and retinoids (Bexarotene, Isotretinoin,Tretinoin (ATRA). For example, the subject compounds may advantageouslybe used in combination with a pyrimidine antagonist such as Gemcitabinefor the treatment of solid tumors such as pancreatic cancers such aspancreatic adenocarcinoma.

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemoprotective agent.Chemoprotective agents act to protect the body or minimize the sideeffects of chemotherapy. Examples of such agents include, but are notlimited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administeredin combination with radiation therapy. Radiation is commonly deliveredinternally (implantation of radioactive material near cancer site) orexternally from a machine that employs photon (x-ray or gamma-ray) orparticle radiation. Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

It will be appreciated that compounds of the invention can be used incombination with an immunotherapeutic agent. One form of immunotherapyis the generation of an active systemic tumor-specific immune responseof host origin by administering a vaccine composition at a site distantfrom the tumor. Various types of vaccines have been proposed, includingisolated tumor-antigen vaccines and anti-idiotype vaccines. Anotherapproach is to use tumor cells from the subject to be treated, or aderivative of such cells (reviewed by Schirrmacher et al. (1995) J.Cancer Res. Clin. Oncol., 121:487). In U.S. Pat. No. 5,484,596, HannaJr. et al. claim a method for treating a resectable carcinoma to preventrecurrence or metastases, comprising surgically removing the tumor,dispersing the cells with collagenase, irradiating the cells, andvaccinating the patient with at least three consecutive doses of about10⁷ cells.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more adjunctivetherapeutic agents. Examples of suitable agents for adjunctive therapyinclude a 5HT₁ agonist, such as a triptan (e.g. sumatriptan ornaratriptan); an inhibitor of the phosphoinositol-3-kinase (PI3K)family; an inhibitor of the mammalian target of rapamycin (mTOR); aninhibitor of Bcr-Abl; an adenosine A1 agonist; an EP ligand; an NMDAmodulator, such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g. an NKi antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentinand related compounds; a tricyclic antidepressant (e.g. amitryptilline);a neuron stabilising antiepileptic drug; a mono-aminergic uptakeinhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOSinhibitor; an inhibitor of the release, or action, of tumour necrosisfactor alpha; an antibody therapy, such as a monoclonal antibodytherapy; an antiviral agent, such as a nucleoside inhibitor (e.g.lamivudine) or an immune system modulator (e.g. interferon); an opioidanalgesic; a local anaesthetic; a stimulant, including caffeine; anH₂-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g.omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; anantiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine,phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine);an antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, ordextramethorphan); a diuretic; or a sedating or non-sedatingantihistamine.

The compounds may also be used in the treatment of a disorder involving,relating to or, associated with dysregulation of histone deacetylase(HDAC). There are a number of disorders that have been implicated by orknown to be mediated at least in part by HDAC activity, where HDACactivity is known to play a role in triggering disease onset, or whosesymptoms are known or have been shown to be alleviated by HDACinhibitors. Disorders of this type that would be expected to be amenableto treatment with the compounds of the invention include the followingbut not limited to: Anti-proliferative disorders (e.g. cancers);Neurodegenerative diseases including Huntington's Disease, Polyglutaminedisease, Parkinson's Disease, Alzheimer's Disease, Seizures,Striatonigral degeneration, Progressive supranuclear palsy, Torsiondystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gillesde la Tourette syndrome, Diffuse Lewy body disease, Progressivesupranuclear palsy, Pick's disease, intracerebral hemorrhage, Primarylateral sclerosis, Spinal muscular atrophy, Amyotrophic lateralsclerosis, Hypertrophic interstitial polyneuropathy, Retinitispigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia,Progressive ataxia and Shy-Drager syndrome; Metabolic diseases includingType 2 diabetes; Degenerative Diseases of the Eye including Glaucoma,Age-related macular degeneration, Rubeotic glaucoma; Inflammatorydiseases and/or Immune system disorders including Rheumatoid Arthritis(RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Hostdisease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease,inflammatory bowel disease Colitis Ulcerosa, Alcoholic hepatitis,Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosingspondylitis, Membranous glomerulopathy, Discogenic pain, Systemic LupusErythematosus; Disease involving angiogenesis including cancer,psoriasis, rheumatoid arthritis; Psychological disorders includingbipolar disease, schizophrenia, mania, depression and dementia;Cardiovascular Diseases including the prevention and treatment ofischemia-related or reperfusion-related vascular and myocardial tissuedamage, heart failure, restenosis and arteriosclerosis; Fibroticdiseases including liver fibrosis, cystic fibrosis and angiofibroma;Infectious diseases including Fungal infections, such as candidiasis orCandida Albicans, Bacterial infections, Viral infections, such as HerpesSimplex, poliovirus, rhinovirus and coxsackievirus, Protozoalinfections, such as Malaria, Leishmania infection, Trypanosoma bruceiinfection, Toxoplasmosis and coccidlosis and Haematopoietic disordersincluding thalassemia, anemia and sickle cell anemia.

Compounds of the invention inhibit angiongenesis and are thereforeuseful in the treatment of diseases or conditions mediated byangiogenesis such as tumors, in particular solid tumors such as colon,lung, pancreatic, ovarian, breast and glioma. Furthermore, compounds ofthe invention are useful for treating macular degeneration, e.g., wetage-related macular degeneration. Compounds of the invention are alsouseful for treating inflammatory/immune diseases such as Crohn'sdisease, inflammatory bowel disease, Sjogren's syndrome, asthma, organtransplant rejection, systemic lupus erythmatoses, psoriatic arthritis,psoriasis and multiple sclerosis. The compounds can also be used for thedown-regulation of hair growth or as a depilatory for cosmetic purposesor in the treatment of hirsutism.

The invention encompasses pharmaceutical compositions comprisingpharmaceutically acceptable salts of the compounds of the invention asdescribed above. The invention also encompasses solvates of thecompounds of the invention and pharmaceutical compositions comprisingsuch solvates, such as hydrates, methanolates or ethanolates. The term“solvate” refers to a solid, preferably crystalline, form of a compoundwhich includes the presence of solvent molecules within the crystallattice. A solvate of a compound comprising a given solvent is typicallyprepared by crystallization of the compound from that solvent. Solvatescan include a variety of solvents, including water, methanol andethanol. The term “hydrate” refers to a solvate in which the solvent iswater, and includes, but is not limited to, hemihydrate, monohydrate,dihydrate, trihydrate and the like. The invention further encompassespharmaceutical compositions comprising any solid or liquid physical formof the compound of the invention, including crystalline and crystallinesolvate forms. For example, the compounds can be in a crystalline form,in amorphous form, and have any particle size. The particles may bemicronized, or may be agglomerated, particulate granules, powders, oils,oily suspensions or any other -solid or liquid physical form.

The compounds of the invention, and derivatives, fragments, analogs,homologs, pharmaceutically acceptable salts or solvates thereof can beincorporated into pharmaceutical compositions suitable foradministration, together with a pharmaceutically acceptable carrier orexcipient. Such compositions typically comprise a therapeuticallyeffective amount of any of the compounds above, and a pharmaceuticallyacceptable carrier. Preferably, the effective amount when treatingcancer is an amount effective to selectively induce terminaldifferentiation of suitable neoplastic cells and less than an amountwhich causes toxicity in a patient.

Compounds of the invention may be administered by any suitable means,including, without limitation, parenteral, intravenous, intramuscular,subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary,transdermal, topical, vaginal, rectal, and transmucosal administrationsor the like. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Pharmaceutical preparations include a solid, semisolid orliquid preparation (tablet, pellet, troche, capsule, suppository, cream,ointment, aerosol, powder, liquid, emulsion, suspension, syrup,injection etc.) containing a compound of the invention as an activeingredient, which is suitable for selected mode of administration. Inone embodiment, the pharmaceutical compositions are administered orally,and are thus formulated in a form suitable for oral administration,i.e., as a solid or a liquid preparation. Suitable solid oralformulations include tablets, capsules, pills, granules, pellets,sachets and effervescent, powders, and the like. Suitable liquid oralformulations include solutions, suspensions, dispersions, emulsions,oils and the like. In one embodiment of the present invention, thecomposition is formulated in a capsule. In accordance with thisembodiment, the compositions of the present invention comprise inaddition to the active compound and the inert carrier or diluent, a hardgelatin capsule.

Any inert excipient that is commonly used as a carrier or diluent may beused in the formulations of the present invention, such as for example,a gum, a starch, a sugar, a cellulosic material, an acrylate, ormixtures thereof. A preferred diluent is microcrystalline cellulose. Thecompositions may further comprise a disintegrating agent (e.g.,croscarmellose sodium) and a lubricant (e.g., magnesium stearate), andmay additionally comprise one or more additives selected from a binder,a buffer, a protease inhibitor, a surfactant, a solubilizing agent, aplasticizer, an emulsifier, a stabilizing agent, a viscosity increasingagent, a sweetener, a film forming agent, or any combination thereof.Furthermore, the compositions of the present invention may be in theform of controlled release or immediate release formulations.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfate; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

In addition, the compositions may further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), buffers (e.g., tris-HCl, acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol), a glidant(e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosityincreasing agents (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citricacid), flavoring agents (e.g., peppermint, methyl salicylate, or orangeflavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens),lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol,sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral compositions in dosageunit form for ease of administration and uniformity of dosage. Dosageunit form as used herein refers to physically discrete units suited asunitary dosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Daily administration may be repeated continuously for a period ofseveral days to several years. Oral treatment may continue for betweenone week and the life of the patient. Preferably the administration maytake place for five consecutive days after which time the patient can beevaluated to determine if further administration is required. Theadministration can be continuous or intermittent, e.g., treatment for anumber of consecutive days followed by a rest period. The compounds ofthe present invention may be administered intravenously on the first dayof treatment, with oral administration on the second day and allconsecutive days thereafter.

The preparation of pharmaceutical compositions that contain an activecomponent is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than anamount that would cause toxicity in the patient. In certain embodiments,the amount of the compound that is administered to the patient is lessthan the amount that causes a concentration of the compound in thepatient's plasma to equal or exceed the toxic level of the compound.Preferably, the concentration of the compound in the patient's plasma ismaintained at about 10 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 25 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 50 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 100 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 1000 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 2500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 5000 nM. Theoptimal amount of the compound that should be administered to thepatient in the practice of the present invention will depend on theparticular compound used and the type of cancer being treated.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” or “aliphatic” is non-aromatic moiety that may besaturated (e.g. single bond) or contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic, contain carbon, hydrogen or,optionally, one or more heteroatoms and may be substituted orunsubstituted. An aliphatic group, when used as a linker, preferablycontains between about 1 and about 24 atoms, more preferably betweenabout 4 to about 24 atoms, more preferably between about 4-12 atoms,more typically between about 4 and about 8 atoms. An aliphatic group,when used as a substituent, preferably contains between about 1 andabout 24 atoms, more preferably between about 1 to about 10 atoms, morepreferably between about 1-8 atoms, more typically between about 1 andabout 6 atoms. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl groups described herein.

The term “substituted carbonyl” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain asubstituted carbonyl include aldehydes, ketones, carboxylic acids,amides, esters, anhydrides, etc. The term “carbonyl moiety” refers togroups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide).

The term “acyl” refers to hydrogen, alkyl, partially saturated or fullysaturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” embraces linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about ten carbon atoms. Most preferred are lower alkyl radicalshaving one to about eight carbon atoms. Examples of such radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkenylradicals are “lower alkenyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyland 4-methylbutenyl. The terms “alkenyl”, and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” embraces linear or branched radicals having at leastone carbon-carbon triple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl,1-butyne, 2-butynyl and 1-pentynyl.

The term “cycloalkyl” embraces saturated carbocyclic radicals havingthree to about twelve carbon atoms. The term “cycloalkyl” embracessaturated carbocyclic radicals having three to about twelve carbonatoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to about eight carbon atoms. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkenyl” embraces partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxyradicals attached to the alkyl radical, that is, to form monoalkoxyalkyland dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”embrace saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” embraces unsaturated heterocyclyl radicals.Examples of heteroaryl radicals include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” embraces heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radicals.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkylthio radicals have alkyl radicals are “loweralkylthio” radicals having one to about ten carbon atoms. Most preferredare alkylthio radicals having lower alkyl radicals of one to about eightcarbon atoms. Examples of such lower alkylthio radicals are methylthio,ethylthio, propylthio, butylthio and hexylthio.

The terms “aralkyl” or “arylalkyl” embrace aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” embraces aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” embrace aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” embraces alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred aminoalkyl radicals are “lower aminoalkyl”that have alkyl radicals having one to about ten carbon atoms. Mostpreferred are aminoalkyl radicals having lower alkyl radicals having oneto eight carbon atoms. Examples of such radicals include aminomethyl,aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “linker” means an organic moiety that connects two parts of acompound. Linkers typically comprise a direct bond or an atom such asoxygen or sulfur, a unit such as NR₂, C(O), C(O)NH, SO, SO₂, SO₂NH or achain of atoms, such as substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl,heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl,alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl,alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl,alkenylheteroarylalkyl, alkenylheteroarylalkenyl,alkenylheteroarylalkynyl, alkynylheteroarylalkyl,alkynylheteroarylalkenyl, alkynylheteroarylalkynyl,alkylheterocyclylalkyl, alkylheterocyclylalkenyl,alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl,alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl,alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl,alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or moremethylenes can be interrupted or terminated by O, S, S(O), SO₂, N(R₂),C(O), substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclic; where R₂ ishydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment,the linker B is between 1-24 atoms in length, preferably 4-24 atoms inlength, preferably 4-18 atoms in length, more preferably 4-12 atoms inlength, and most preferably about 4-10 atoms in length. In someembodiments, the linker is a C(O)NH(alkyl) chain or an alkoxy chain. Itis to be understood that an asymmetric linker, such as alkylaryl, canconnect two structurally distinct moieties in either of its two possibleorientations.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkyl sulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties are defined and referred to throughoutcan be univalent chemical moieties (e.g., alkyl, aryl, etc.) ormultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

As used herein, the term “aberrant proliferation” refers to abnormalcell growth.

The phrase “adjunctive therapy” encompasses treatment of a subject withagents that reduce or avoid side effects associated with the combinationtherapy of the present invention, including, but not limited to, thoseagents, for example, that reduce the toxic effect of anticancer drugs,e.g., bone resorption inhibitors, cardioprotective agents; prevent orreduce the incidence of nausea and vomiting associated withchemotherapy, radiotherapy or operation; or reduce the incidence ofinfection associated with the administration of myelosuppressiveanticancer drugs.

The term “angiogenesis,” as used herein, refers to the formation ofblood vessels. Specifically, angiogenesis is a multi-step process inwhich endothelial cells focally degrade and invade through their ownbasement membrane, migrate through interstitial stroma toward anangiogenic stimulus, proliferate proximal to the migrating tip, organizeinto blood vessels, and reattach to newly synthesized basement membrane(see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)).Anti-angiogenic agents interfere with this process. Examples of agentsthat interfere with several of these steps include thrombospondin-1,angiostatin, endostatin, interferon alpha and compounds such as matrixmetalloproteinase (MMP) inhibitors that block the actions of enzymesthat clear and create paths for newly forming blood vessels to follow;compounds, such as .alpha.v.beta.3 inhibitors, that interfere withmolecules that blood vessel cells use to bridge between a parent bloodvessel and a tumor; agents, such as specific COX-2 inhibitors, thatprevent the growth of cells that form new blood vessels; andprotein-based compounds that simultaneously interfere with several ofthese targets.

The term “apoptosis” as used herein refers to programmed cell death assignaled by the nuclei in normally functioning human and animal cellswhen age or state of cell health and condition dictates. An “apoptosisinducing agent” triggers the process of programmed cell death.

The term “cancer” as used herein denotes a class of diseases ordisorders characterized by uncontrolled division of cells and theability of these cells to invade other tissues, either by direct growthinto adjacent tissue through invasion or by implantation into distantsites by metastasis.

The term “compound” is defined herein to include pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, enantiomers,diastereoisomers, racemates and the like of the compounds having aformula as set forth herein.

The term “device” refers to any appliance, usually mechanical orelectrical, designed to perform a particular function.

As used herein, the term “dysplasia” refers to abnormal cell growth, andtypically refers to the earliest form of pre-cancerous lesionrecognizable in a biopsy by a pathologist.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about, e.g. a change in the rate of cell proliferationand/or state of differentiation and/or rate of survival of a cell toclinically acceptable standards. This amount may further relieve to someextent one or more of the symptoms of a neoplasia disorder, including,but is not limited to: 1) reduction in the number of cancer cells; 2)reduction in tumor size; 3) inhibition (i.e., slowing to some extent,preferably stopping) of cancer cell infiltration into peripheral organs;4) inhibition (i.e., slowing to some extent, preferably stopping) oftumor metastasis; 5) inhibition, to some extent, of tumor growth; 6)relieving or reducing to some extent one or more of the symptomsassociated with the disorder; and/or 7) relieving or reducing the sideeffects associated with the administration of anticancer agents.

The term “hyperplasia,” as used herein, refers to excessive celldivision or growth.

The phrase an “immunotherapeutic agent” refers to agents used totransfer the immunity of an immune donor, e.g., another person or ananimal, to a host by inoculation. The term embraces the use of serum orgamma globulin containing performed antibodies produced by anotherindividual or an animal; nonspecific systemic stimulation; adjuvants;active specific immunotherapy; and adoptive immunotherapy. Adoptiveimmunotherapy refers to the treatment of a disease by therapy or agentsthat include host inoculation of sensitized lymphocytes, transferfactor, immune RNA, or antibodies in serum or gamma globulin.

The term “inhibition,” in the context of neoplasia, tumor growth ortumor cell growth, may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention or chemoprevention.

The term “metastasis,” as used herein, refers to the migration of cancercells from the original tumor site through the blood and lymph vesselsto produce cancers in other tissues. Metastasis also is the term usedfor a secondary cancer growing at a distant site.

The term “neoplasm,” as used herein, refers to an abnormal mass oftissue that results from excessive cell division. Neoplasms may bebenign (not cancerous), or malignant (cancerous) and may also be calleda tumor. The term “neoplasia” is the pathological process that resultsin tumor formation.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “proliferation” refers to cells undergoing mitosis.

The phrase “hedgehog related disease or disorder” refers to a disease ordisorder characterized by inappropriate hedgehog signaling activity.Such inappropriate hedgehog signaling activity can occur when Patchedfails to, or inadequately, represses Smoothened (Ptc loss of functionphenotype) and/or when Smoothened is active regardless of Patchedrepression (Smo gain-of function phenotype).

The phrase a “radio therapeutic agent” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.

The term “recurrence” as used herein refers to the return of cancerafter a period of remission. This may be due to incomplete removal ofcells from the initial cancer and may occur locally (the same site ofinitial cancer), regionally (in vicinity of initial cancer, possibly inthe lymph nodes or tissue), and/or distally as a result of metastasis.

The term “treatment” refers to any process, action, application,therapy, or the like, wherein a mammal, including a human being, issubject to medical aid with the object of improving the mammal'scondition, directly or indirectly.

The term “vaccine” includes agents that induce the patient's immunesystem to mount an immune response against the tumor by attacking cellsthat express tumor associated antigens (Teas).

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid or inorganic acid. Examples of pharmaceuticallyacceptable nontoxic acid addition salts include, but are not limited to,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid lactobionic acid or malonic acid or byusing other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention.

“Prodrug”, as used herein, means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of the invention.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed.), “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

As used herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Preferredexamples of such carriers or diluents include, but are not limited to,water, saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds described herein can contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers and/or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta-(β) and gamma-(γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intracisternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes andexamples that illustrate the methods by which the compounds of theinvention may be prepared, which are intended as an illustration onlyand not limiting of the scope of the invention.

General Methods for the Synthesis of Key Intermediates

Synthesis of Intermediates 1) Preparation of1-chloro-2-iodo-4-nitrobenzene (compound 1-3)

2-Chloro-5-nitroaniline (40 g, 232.0 mmol) was added to a solution ofconcentrated sulfuric acid (32 mL) in water (320 mL) with mechanicalstir. The solution was cooled to −5° C. and a solution of sodium nitrite(18.2 g, 0.26 mol) in water (69 mL) was added slowly. The mixture wasstirred for 0.5 h in ice bath and then a solution of potassium iodide(69.3 g, 0.41 mol) in water (277 mL) was added dropwise while keepingthe internal temperature below 5° C. The solution was stirred for 3 h at0° C. followed by extraction with ethyl acetate. The combined organiclayers were washed with saturated Na₂S₂O₃, dried over Na₂SO₄ andconcentrated. The residue was recrystallized from ^(i)PrOH/hexanes (300mL/100 mL) to afford compound 1-3 as a light tan crystalline solid (38g, 58% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.61 (d, J=8.8 Hz, 1H), 8.16(dd, J=8.8 Hz, 2.4 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H).

2) Preparation of 4-chloro-3-iodoaniline (compound 1-4)

A mixture of compound 1-3 (37 g, 0.13 mol), iron powder (29.3 g, 0.52mol), and NH₄Cl (7 g, 0.13 mol) in EtOH/H₂O (200 mL/100 mL) was stirredat 75° C. for 3 h. The reaction mixture was filtered and concentrated toremove most of EtOH. The remaining mixture was extracted with ethylacetate, washed with water and brine, dried over Na₂SO₄. The titledcompound 1-4 was obtained as a yellow solid (32 g, 97% yield) afterconcentration. LCMS: m/z 254.0 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 3.65(br, 2H), 6.58 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.15-7.17 (m, 2H).

3) Preparation of4-chloro-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(compound 1-5)

A mixture of compound 1-4 (10 g, 39.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (20.0 g,79.0 mmol), KOAc (11.6 g, 118.5 mmol), and PdCl₂(dppf) (960 mg, 1 mmol)in 1,4-dioxane (60 mL) was stirred at 105° C. for 8 h under N₂. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby column chromatography (hexanes/dichloromethane: 3/1 to 1/1) to affordcompound 1-5 as a light yellow solid (6.0 g, 60% yield). LCMS: m/z 295.1[M+42]⁺. ¹H NMR (400 MHz, CDCl₃): δ 1.36 (s, 12H), 3.61 (br, 2H), 6.65(dd, J=8.8 Hz, 2.8 Hz, 1H), 7.00 (d, J=2.8 Hz, 1H), 7.11 (d, J=8.8 Hz,1H).

4) Preparation of 4-chloro-3-(pyridine-2-yl)aniline (compound 1-8)

A mixture of compound 1-5 (1.50 g, 5.9 mmol), 2-bromopyridine (1.87 g,11.8 mmol), sodium bicarbonate (1.49 g, 17.8 mmol), PdCl₂(Ph₃P)₂ (100mg, 0.09 mmol) in 1,4-dioxane/water (20 mL/10 mL) was heated at 110° C.overnight. After cooling to room temperature, the mixture was quenchedwith water and extracted with ethyl acetate. The combined organic layerswere washed with water and brine, dried over anhydrous sodium sulfateand evaporated in vacuo. The crude product was purified by columnchromatography (hexanes/ethyl acetate: 3/1) to afford compound 1-8 as ayellow solid (1.38 g, ˜100%). LCMS: m/z 205.1 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 5.32 (s, 2H), 6.61 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.77 (d,J=2.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.35-7.39 (m, 1H), 7.57 (d, J=8.0Hz, 1H), 7.83-7.87 (m, 1H), 8.63-8.65 (m, 1H).

5) Preparation of2-chloro-N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsufonyl)benzamide(compound 1-9)

A mixture of compound 1-5 (1 g, 3.9 mmol),2-chloro-4-(methylsulfonyl)benzoic acid (1.1 g, 4.7 mmol) andN,N-Diisopropylethylamine (1 g, 7.8 mmol) andO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (2.6g, 7.8 mmol) in dichloromethane (20 mL) was stirred at room temperatureovernight. The reaction mixture was quenched with water, filtered. Thesolid was collected and dried in vacuo to afford compound 1-9 as a whitesolid (1.2 g, 65% yield). LCMS: m/z 470.1 [M+1]⁺. ^(°1)H NMR: (400 MHz,DMSO-d₆): δ 1.32 (s, 12H), 3.35 (s, 3H), 7.43 (d, J=8.8 Hz, 1H), 7.81(dd, J=8.8 Hz, 2.8 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.98-8.01 (m, 2H),8.12 (d, J=1.6 Hz, 1H), 10.82 (s, 1H).

6) Preparation of 2-chloro-5-nitro-N-(2-nitrophenyl)benzamide (compound2-2)

To a solution of 2-nitroaniline (5.0 g, 0.036 mol) in CH₃CN (50 mL) wasadded a solution of 2-chloro-5-nitrobenzoyl chloride (8.0 g, 0.037 mol)in CH₃CN (10 mL) dropwise while keeping the internal temperature below25° C. under N₂. When addition was complete the reaction mixture washeated at 75° C. for 1 h. The mixture was cooled to 0° C. and filtered.The solid was rinsed with cold CH₃CN to afford 2-2 as a light yellowsolid (5.3 g, 50%).

7) Preparation of 3-(1H-benzo[d]imidazol-2-yl)-4-chloroaniline (compound2-3)

Compound 2-2 (5.3 g, 0.017 mol) was taken into EtOH (100 mL) and heatedto 40° C. When the internal temperature reached 40° C., 1^(st) aliquotSnCl₂/HCl (3 vol respectively, divided into 3 portions) was added. Thereaction mixture was heated to 60° C. and the 2^(nd) aliquot ofSnCl₂/HCl was added. The reaction mixture was heated to 80° C. and the3^(rd) aliquot SnCl₂/HCl was added and continued to reflux 2 h. Thereaction mixture was cooled to 0° C. and NaOH (1N aqueous solution) wasadded below 10° C. to adjust pH to 12-13. The mixture was diluted withEA and water. The organic layer was washed with brine and concentrated.The crude product was purified by column chromatography eluted withdichloromethane/methanol (60:1) to afford compound 2-3 as a yellow solid(2.7 g, 68% yield). LCMS: m/z 244.1[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ5.48 (s, 2H), 6.71 (d, J=8.8 Hz, 1H), 7.13 (s, 1H), 7.21-7.24 (m, 3H),7.57 (br, 1H), 7.64 (br, 1H), 12.52 (s, 1H).

Example 1: Preparation of(E)-2-chloro-N-(4-chloro-3-(5-(3-(hydroxyamino)-3-oxoprop-1-enyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide(compound 1) Step 1a. (E)-Methyl 3-(6-bromopyridin-3-yl)acrylate(compound 1001-1)

A mixture of 6-bromonicotinaldehyde (500 mg, 2.7 mmol) and methyl(triphenylphosphoranylidene) (1 g, 3.2 mmol) in dichloromethane (10 mL)was stirred at room temperature for 1 h. The mixture was concentrated invacuo and filtered. The solid was washed with hexanes to afford crudecompound 1001-1 as a white solid (1.5 g).

Step 1b.(E)-Methyl-3-(6-(2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)phenyl)pyridin-3-yl)acrylate (1002-1)

A mixture of 1001 (121 mg, 0.5 mmol), 1-9 (200 mg, 0.4 mmol),Pd(PPh₃)₂Cl₂ (30 mg) in 1,4-dioxane (6 mL) and aq NaHCO₃ (2 mL) wasstirred at 110° C. for 3 h under N₂. After cooling to room temperature,the reaction mixture was quenched with water, extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate, evaporated in vacuo. The crudeproduct was purified by column chromatography (methanol/dichloromethane:1/20) to afford compound 1002 as a pale yellow solid (160 mg, 74%yield). ¹H NMR (400 MHz, CDCl₃): δ 3.09 (s, 3H), 3.85 (s, 3H), 6.57 (d,J=16.0 Hz, 1H), 7.44-7.48 (m, 1H), 7.52-7.55 (m, 1H), 7.62-7.67 (m, 1H),7.73 (d, J=16.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.81-7.86 (m, 2H), 7.89(s, 1H), 7.89-7.95 (m, 2H), 8.03 (d, J=1.2 Hz, 1H), 8.14 (s, 1H), 8.80(d, J=2.0 Hz, 1H).

Step 1c.(E)-2-Chloro-N-(4-chloro-3-(5-(3-(hydroxyamino)-3-oxoprop-1-enyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide(compound 1)

A mixture of NH₂OH.HCl (80 g, 1.15 mol) in MeOH (400 mL) was heated at60-65° C. while stirring to form a clear solution. After additional 1 hat reflux, it was cooled to 0-10° C. To the reaction mixture apre-formed solution of KOH (96 g, purity >85%) in MeOH (237 mL)(prepared by adding KOH in portion to methanol at 0-10° C.) was addeddropwise while maintaining internal temperature <10° C. The resultingmixture was continued to stir at 0-10° C. for 30 min. The suspension waspoured into pressure equalizing addition funnel (1 L) pre-packed withanhydrous Na₂SO₄ (700 g) and let it sit for 0.5 h. The clear filtratewas collected as NH₂OH methanolic solution.

A mixture of 1002 (150 mg, 0.3 mmol) in NH₂OH methanolic solution (5 mL,1.79M) was stirred at room temperature for 3˜4 h. The reaction mixturewas adjusted pH to 6-7 with 1.2 M HCl and concentrated. The residue wastriturated with water and filtered, dried in vacuo to afford compound 1as an off white solid (90 mg, 60% yield). M.p: 185˜187° C. LCMS: m/z506.1[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.35 (s, 3H), 6.65 (d, J=16.0Hz, 1H), 7.55-7.61 (m, 2H), 7.74-7.78 (m, 2H), 7.91 (d, J=8.0 Hz, 1H),8.01 (d, J=8.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.11-8.13 (m, 2H), 8.90(s, 1H), 10.90 (br, 1H), 10.96 (s, 1H).

Example 2: Preparation of 6-(2-Chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)phenyl)-N-hydroxynicotinamide (compound 5) Step 2a. Methyl6-bromonicotinate (compound 1001-5)

To a solution of 6-bromonicotinic acid (500 mg, 2.5 mmol) indichloromethane (10 mL) and THF (5 mL) was added oxalyl chloride (1.4mL, 0.016 mol) followed by addition of one drop of DMF. The mixture wasstirred at room temperature for 1 h. After removal of solvent, theresidue was dissolved in anhydrous methanol (5 mL) and continued to stirfor 10 min. The reaction mixture was quenched with ice water andfiltered to afford 1001-5 as a pale yellow solid (212 mg, 40%). LCMS:m/z 213.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 3.96 (s, 3H), 7.42 (d,J=8.4 Hz, 1H), 8.25 (dd, J=8.0 Hz, 2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).

Step 2b. Methyl6-(2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)phenyl) nicotinate(compound 1002-5)

A mixture of compound 1001-5 (200 mg, 0.9 mmol), 1-9 (367 mg, 0.8 mmol)and Pd(PPh₃)₄ (21 mg, 0.018 mmol) in saturated NaHCO₃ (2 mL) and1,4-dioxane (6 mL) was stirred at 100° C. for 3 h. To the reactionmixture was added NaOH (37 mg, 0.9 mmol) and stirred for 0.5 h. Thereaction mixture was adjusted pH to 6 with 1.2M HCl and extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate. The methyl ester was hydrolyzed duringthis reaction condition, and the obtained crude acid product (365 mg)(LCMS: m/z 465.1 [M+1]⁺) was used for the next step without furtherpurification. The mixture of the crude acid product (365 mg, 0.8 mmol)in MeOH (15 mL) and H₂SO₄ (0.25 mL) was stirred at 85° C. for 1 h. Thereaction mixture was concentrated. The residue was partitioned betweenwater and ethyl acetate. The organic layers were washed with water andbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas purified by column chromatography (dichloromethane/methanol: 20/1)to afford 1002-5 as a white solid (176 mg, 39% yield via two steps).LCMS: m/z 479.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 3.07 (s, 3H), 3.99(s, 3H), 7.52 (d, J=8.8 Hz, 1H), 7.81-7.86 (m, 4H), 7.88 (dd, J=8.8 Hz,2.8 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 8.37 (dd, J=8.4 Hz, 2.4 Hz, 1H),8.62 (s, 1H), 9.17 (d, J=1.2 Hz, 1H).

Step 2c.6-(2-Chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)phenyl)-N-hydroxynicotinamide(compound 5)

A mixture of 1002-5 (176 mg, 0.4 mmol) in NH₂OH methanolic solution (5mL, 1.79 M) was stirred at room temperature for 1 h. The reactionmixture was adjusted pH to 6˜7 with 1.2 M HCl. The reaction mixture wasfiltered, washed with water, dried in vacuo to afford compound 5 as anoff-white solid (120 mg 70% yield). M.p.: 190˜193° C. LCMS: m/z 480.2[M+1]⁺. HNMR: (400 MHz, DMSO-d₆): δ 3.35 (s, 3H), δ 7.61 (d, J=8.4 Hz,1H), 7.76 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.91 (d,J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H),8.13 (d, J=1.6 Hz, 1H), 8.22 (dd, J=8.0 Hz, 2.0 Hz, 1H), 9.02 (d, J=1.6Hz, 1H), 9.28 (s, 1H), 10.96 (s, 1H), 11.48 (s, 1H).

Example 3: Preparation of2-[2-Chloro-5-(2-chloro-4-methanesulfonyl-benzoylamino)-phenyl]-pyrimidine-5-carboxylicacid hydroxyamide (compound 7) Step 3a. 2-Chloro-pyrimidine-5-carboxylicacid methyl ester (compound 1001-7)

A mixture of NaH (27 g, 60% in mineral oil, 0.675 mol) in anhydrous1,2-dimethoxyethane (300 mL) was heated to 40-50° C. Methyl3,3-dimethoxy propionate (100 g, 0.675 mol) was added dropwise. Theresulting mixture was stirred for 0.5 h and anhydrous methyl formate (81g, 1.35 mol) was added dropwise at 40-50° C. The resulting mixture wasstirred at 40-50° C. (inner temperature) for 2 h before it was cooled to0° C. The reaction mixture was allowed to warm to 25° C. slowly andstirred overnight. Et₂O (150 mL) was added and stirred for 30 min. Theresulting suspension was filtered. The solid was washed with Et₂O (100mL), collected and dried to afford sodium(Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate as an off-whitesolid (82 g, 61%). LCMS: m/z 130.8 [M+1]⁺. ¹HNMR (400 MHz, CD₃OD): δ3.36 (s, 6H), 3.60 (s, 3H), 5.34 (s, 1H), 8.92 (s, 1H).

To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300mL) was added above off-white solid (80 g, 0.40 mol). The resultingmixture was heated at 100° C. for 1 h. The reaction mixture was filteredbefore cooled. The filter cake was washed with 50 mL of DMF and thecombined filtrate was concentrated to leave a residue which wassuspended in cold EtOH and washed with cold EtOH (50 mL) to afford theintermediate 2-amino-pyrimidine-5-carboxylic acid methyl ester as ayellow solid (38 g, 61.5%). LCMS: m/z 154.2 [M+1]⁺, 195.1[M+42]⁺. ¹HNMR(400 MHz, CD₃OD): δ 3.88 (s, 3H), 8.77 (s, 2H).

The above intermediate (7 g, 0.046 mol) was added to a mixture ofconcentrated hydrochloric acid (15.2 mL) and CH₂Cl₂ (60 mL). Aftercooling, ZnCl₂ (18.6 g, 0.138 mol) was added at 15-20° C. The mixturewas stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO₂ (9.5 g,0.138 mol) was added portion wise while keeping the internal temperature5-10° C. The reaction was continued for ˜2 h. The reaction mixture waspoured into ice-water (50 mL). The organic layer was separated and theaqueous phase was extracted with CH₂Cl₂ (30 mL×2). The combined organicextracts were concentrated to afford crude product (4.2 g). The crudecompound was suspended in hexane (20 mL), heated at 60° C. for 30minutes and filtered. The filtrate was concentrated to afford the titledcompound 1001-7 (3.5 g, 44.4%) as an off-white solid. LCMS: m/z214.1[M+42]⁺. ¹HNMR (400 MHz, CDCl₃): δ 4.00 (s, 3H), 9.15 (s, 2H).

Step 3b.2-[2-Chloro-5-(2-chloro-4-methanesulfonyl-benzoylamino)-phenyl]-pyrimidine-5-carboxylicacid methyl ester (compound 1002-7)

A mixture of 1001-7 (200 mg, 1.1 mmol), 1-9 (756 mg, 1.6 mmol) andPd(PPh₃)₄ (60 mg, 0.05 mmol) in saturated NaHCO₃ (2 mL) and DMSO (6 mL)was stirred at 100° C. for 3 h. After cooling to room temperature, NaOH(43 mg, 1.1 mmol) was added to reaction solution and stirred for 0.5 h.The reaction mixture was extracted with ethyl acetate. The aqueous layerwas adjusted pH to 6 with 1.2 M HCl and extracted with ethyl acetate.The combined organic layers were washed with water and brine, dried overNa₂SO₄, concentrated to afford crude acid (300 mg) without furtherpurification.

The mixture of the crude acid (300 mg) in MeOH (15 mL) and H₂SO₄ (0.25mL) was stirred at 85° C. for 1 h. After removal of solvent, the residuewas partitioned between water and ethyl acetate. The combined organiclayers were washed with water and brine, dried over Na₂SO₄. The crudeproduct was purified by column chromatography (hexanes/ethyl acetate:1/1) to afford compound 1002-7 as a white solid (160 mg, 78% yield viatwo steps). LCMS: m/z 480.2[M+1]⁺. ¹H NMR: (400 MHz, CDCl₃): δ 3.36 (s,3H), 3.96 (s, 3H), 7.65 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 Hz, J=2.4 Hz,1H), 7.93 (d, J=8.0 Hz, 1H), 8.02 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d,J=1.2 Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 9.40 (s, 2H), 11.02 (s, 1H).

Step 3c.2-[2-Chloro-5-(2-chloro-4-methanesulfonyl-benzoylamino)-phenyl]-pyrimidine-5-carboxylicacid hydroxyamide (compound 7)

A mixture of compound 1002-7 (160 mg, 0.3 mmol) in NH₂OH methanolicsolution (5 mL, 1.79 M) was stirred at room temperature for 1 h. Thereaction mixture was adjusted pH to 6˜7 with 1.2 M HCl and concentrated.The residue was triturated with water and filtered. The crude productwas purified by prep-HPLC to afford compound 7 as an off-white solid (28mg, 18% yield). M.p.: 170˜172° C. LCMS: m/z 481.1 [M+1]⁺. ¹H NMR: (400MHz, DMSO-d₆): δ 3.35 (s, 3H), 7.63 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8Hz, 2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz,1H), 8.14 (d, J=1.6 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 9.23 (s, 2H), 11.01(s, 1H).

Example 4:2-Chloro-N-{4-chloro-3-[5-(6-hydroxycarbamoyl-hexyloxy)-pyridin-2-yl]-phenyl}-4-methanesulfonyl-benzamide(compound 23) Step 4a. 6-Bromo-pyridin-3-ol (compound 2002)

3-Amino-6-bromopyridine (1 g, 5.8 mmol) was dissolved in HBF₄ (3.6 mL,40% aq) and water (3 mL). To the cooled brownish solution under anice-bath was added dropwise NaNO₂ (441 mg, 6.4 mmol) solution in water(3 mL). The resulting mixture was stirred for 1 h at this temperature.After addition of water (3 mL), the mixture was stirred at 100° C. for3.5 h. The reaction mixture was neutralized by aqueous NaHCO₃ (5%) andextracted with ethyl acetate. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄ and evaporated invacuo. The residue was purified by column chromatography (hexanes/ethylacetate: 9/1) to afford compound 2002 as a white solid (270 mg, 27%yield). LCMS: m/z 174.0 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 6.65 (br,1H), 7.13 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.03 (d,J=3.2 Hz, 1H).

Step 4b. 7-(Pyridin-3-yloxy)-heptanoic acid ethyl ester (compound2003-23)

A mixture of 2002 (270 mg, 1.5 mmol), ethyl 7-bromoheptanoate (736 mg,3.1 mmol) and K₂CO₃ (430 mg, 3.1 mmol) in DMF (10 mL) was stirred at 75°C. for 1 h. The solution was partitioned between water and ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous Na₂SO₄ and evaporated in vacuo. The residue waspurified by column chromatography (hexanes/ethyl acetate: 20/1) toafford compound 2003-23 as a white solid (440 mg, 86% yield). LCMS: m/z330.1 [M+1]⁺. ¹H NMR: (400 MHz, CDCl₃): δ 1.25 (t, J=7.2 Hz, 3H),1.36-1.52 (m, 4H), 1.62-1.68 (m, 2H), 1.76-1.83 (m, 2H), 2.31 (t, J=7.2Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 7.08 (dd, J=8.8Hz, 3.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H).

Step 4c.7-{6-[2-Chloro-5-(2-chloro-4-methanesulfonyl-benzoylamino)-phenyl]-pyridin-3-yloxy}-heptanoicacid ethyl ester (compound 2004-23)

A mixture of 2003-23 (168 mg, 0.51 mmol), 1-9 (200 mg, 0.43 mmol) andPd(PPh₃)₄ (24.6 mg, 0.03 mmol) in saturated NaHCO₃ (2 mL) and1,4-dioxane (6 mL) was stirred at 100° C. for 3 h. The solution waspartitioned between water and ethyl acetate. The combined organic layerswere washed with water and brine, dried over anhydrous Na₂SO₄ andevaporated in vacuo. The residue was purified by column chromatography(dichloromethane/methanol: 100/1) to afford 2004-23 as a white solid(130 mg, 43% yield). LCMS: m/z 593.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ1.26 (t, J=7.2 Hz, 3H), 1.37-1.54 (m, 4H), 1.63-1.71 (m, 2H), 1.78-1.85(m, 2H), 2.32 (t, J=7.2 Hz, 2H), 3.00 (s, 3H), 3.98 (t, J=6.4 Hz, 2H),4.12 (q, J=7.2 Hz, 2H), 7.19 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.58 (d, J=1.2Hz, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.69 (dd, J=8.0Hz, 1.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 8.02(dd, J=8.8 Hz, 2.8 Hz, 1H), 8.05 (d, J=2.8 Hz, 1H), 9.88 (s, 1H).

Step 4d.2-Chloro-N-{4-chloro-3-[5-(6-hydroxycarbamoyl-hexyloxy)-pyridin-2-yl]-phenyl}-4-methanesulfonyl-benzamide(compound 23)

A mixture of 2004-23 (130 mg, 0.22 mmol) in NH₂OH methanolic solution (5mL, 1.79 M) was stirred at room temperature for 1 h. The reactionmixture was adjusted pH to 6-7 with 1.2 M HCl. The resulting mixture wasfiltered. The collected solid was purified by prep-HPLC to affordcompound 23 as a white solid (27 mg, 21% yield). M.p.: 140-145° C. LCMS:m/z 580.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.29-1.35 (m, 2H),1.40-1.47 (m, 2H), 1.49-1.56 (m, 2H), 1.72-1.78 (m, 2H), 1.96 (t, J=7.2Hz, 2H), 3.35 (s, 3H), 4.10 (t, J=6.4 Hz, 2H), 7.50 (dd, J=8.8 Hz, 2.8Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8Hz, 2.8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.99-8.02 (m, 2H), 8.13 (d,J=1.6 Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.66 (s, 1H), 10.34 (s, 1H),10.90 (s, 1H).

Example 5:2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(7-(hydroxyamino)-7-oxoheptyl)sulfamoyl)benzamide(compound 59) Step 5a. 4-Amino-2-chlorobenzoic acid (compound 3002)

A mixture of 2-chloro-4-nitrobenzoic acid (5.0 g, 24.8 mmol), ironpowder (8.0 g, 142.9 mmol) and NH₄Cl (7.6 g, 142.9 mmol) in EtOH/water(50/50 mL) was heated at reflux for 2 h. The hot mixture was filteredthrough Celite and washed with ethyl acetate. The mixture was separatedand extracted with ethyl acetate. The combined organic layers werewashed with water and brine, dried over anhydrous sodium sulfate. Thecrude product was purified by column chromatography (hexanes/ethylacetate: 5/1, 3/1, 1/1) to afford compound 3002 as a white solid (1.0 g,24% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 6.04 (s, 2H), 6.49 (dd, J=8.4Hz, 2.0 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 12.21(br, 1H).

Step 5b. 2-Chloro-4-(chlorosulfonyl)benzoic acid (compound 3003)

To a solution of 3002 (1.00 g, 5.4 mmol) in HOAc (20 mL) was added conc.HCl (5 mL) at 0° C. After 15 min, NaNO₂ aqueous solution (1.10 g, 16.2mmol in water 4.5 mL) was added dropwise at −5˜−10° C. and continued tostir at this temperature for 45 min.

The above reaction mixture was added dropwise to cuprous chloride (0.14g, 1.4 mmol) and saturated sulfur dioxide in acetic acid (40 mL) at 0°C. After addition was complete the resulting mixture was warmed to 10°C. and stirred for 30 min. The reaction mixture was quenched with icewater and extracted with ethyl acetate. The combined organic layers werewashed with water and brine, dried over anhydrous sodium sulfate. Thecrude product was purified by column chromatography(dichloromethane/methanol: 100/2, 100/5, 100/10) to afford compound 3003as an off-white solid (500 mg, 34% yield).

Step 5c. 2-Chloro-4-(N-(7-ethoxy-7-oxoheptyl)sulfamoyl)benzoic acid(compound 3004-59)

To a mixture of ethyl 7-aminoheptanoate hydrochloride (777 mg, 3.7 mmol)and N, N-diisopropylethylamine (4.0 g, 31.2 mmol) in dichloromethane (80mL) was added compound 3003 (1.0 g, 3.9 mmol). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was adjustedpH to 6˜7 with 2M HCl and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over anhydroussodium sulfate. The crude product was purified by column chromatography(dichloromethane/methanol: 100/2, 100/5, 100/10) to afford compound3004-59 as a white solid (520 mg, 44% yield). LCMS: m/z 392.1 [M+1]⁺. ¹HNMR (400 MHz, CDCl₃): δ 1.25-1.33 (m, 7H), 1.44-1.62 (m, 4H), 2.28 (t,J=7.2 Hz, 2H), 2.98-3.02 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 5.07 (t, J=5.6Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 8.08 (d, J=8.0 Hz, 1H).

Step 5d. Ethyl7-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)heptanoate (3005-59)

A mixture of 3004-59 (520 mg, 1.3 mmol), oxalyl chloride (1.59 g, 12.5mmol) and DMF (0.05 mL) in dichloromethane was stirred at roomtemperature for 2 h. After evaporation, the residue was dissolved indichloromethane, compound 1-8 (244 mg, 1.2 mmol) and N,N-diisopropylethylamine (325 mg, 2.5 mmol) were added. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas quenched with water and extracted with dichloromethane. The combinedorganic layers were washed with water and brine, dried over anhydroussodium sulfate. The crude product was purified by column chromatography(hexanes/ethyl acetate: 5/1, 3/1, 1/1) to afford compound 3005-59 as awhite solid (250 mg, 33% yield). LCMS: m/z 578.2 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 1.13-1.22 (m, 7H), 1.38-1.49 (m, 4H), 2.22-2.27 (m,2H), 2.76 (t, J=6.8 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 7.44-7.47 (m, 1H),7.59 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.74-7.79 (m,1H), 7.85 (s, 2H), 7.91-7.95 (m, 3H), 8.02 (d, J=2.0 Hz, 1H), 8.71 (d,J=4.8 Hz, 1H), 10.93 (s, 1H).

Step 5e.2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(7-(hydroxyamino)-7-oxoheptyl)sulfamoyl)benzamide(compound 59)

A mixture of 3005-59 (150 mg, 0.2 mmol) in NH₂OH methanolic solution (10mL, 1.79 M) was stirred at room temperature for 2.5 h. TLC showedreaction complete. The reaction mixture was adjusted pH to 5˜6 with 2 MHCl, concentrated. The residue was triturated with water and filtered,purified by prep-HPLC to afford compound 59 as a white solid (46 mg,32%). M.p.: 158.7˜159.3° C. LCMS: m/z 565.2 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 1.14-1.23 (m, 2H), 1.36-1.46 (m, 4H), 1.91 (t, J=7.2 Hz,2H), 2.77 (q, J=6.4 Hz, 2H), 3.40-3.47 (m, 2H), 7.44-7.47 (m, 1H), 7.58(d, J=8.8H, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.4 Hz, 2.4 Hz,1H), 7.83-7.85 (m, 3H), 7.91-7.95 (m, 2H), 8.02 (d, J=2.4 Hz, 1H), 8.71(d, J=4.8 Hz, 1H), 10.32 (s, 1H), 10.89 (s, 1H).

Example 6:2-{4-[2-Chloro-4-(4-chloro-3-pyridin-2-yl-phenylcarbamoyl)-benzenesulfonyl]-piperazin-1-yl}-pyrimidine-5-carboxylicacid hydroxyamide (compound 86) Step 6a.(Z)-ethyl-2-(ethoxymethyl)-3-methoxyacrylate (Compound 4002)

Sodium (27.6 g, 1.2 mol) was added to hexane (400 mL) and ethanol (27 g,1.17 mol) was added dropwise at room temperature. The mixture wasstirred at room temperature for 1 h. Then ethyl 3-ethoxypropanoate (88.0g, 602 mmol) was added dropwise at 0° C. followed by ethyl formate (90g, 1.22 mol). The reaction mixture was stirred at 0° C. for 2 h. anddimethyl sulfate (160 g, 1.27 mol) was added dropwise at the sametemperature. The resulting mixture was heated at 50° C. overnight,filtered, and washed with hexane (300-500 mL). To the combined filtratewas added triethylammonium chloride (80 g, 0.58 mol) and sodiumhydroxide (14.00 g, 0.35 mol). The mixture was stirred at roomtemperature for 4 h and filtered. The filtrate was washed with water,dried over Na₂SO₄ and concentrated. The residue was purified bydistillation to give the desired compound 4002 (63.5 g, 56%) as acolorless oil. LCMS: m/z 211 [M+23]⁺. ¹H NMR (400 MHz, CDCl₃): δ 1.20(t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 3.50 (q, J=7.2 Hz, 2H), 3.88(s, 3H), 4.20 (m, 4H), 7.45 (s, 1H).

Step 6b. Ethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Compound 4003)

A mixture of compound 4002 (63.5 g, 337 mmol), urea (18.7 g, 312 mmol)and concentrated hydrochloric acid (16 mL) in ethanol (300 mL) washeated at reflux overnight. After evaporating the most of ethanol (˜250mL), the resulting suspension was filtered, washed with small amount ofethanol, and dried to give compound 4003 (23.5 g, 44%) as a white solid.LCMS: m/z 171 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=7.2 Hz, 3H),4.19 (m, 4H), 5.28 (s, 1H), 7.21 (d, J=5.6 Hz, 1H), 7.40 (s, 1H).

Step 6c. Ethyl 2-oxo-1,2-dihydropyrimidine-5-carboxylate (Compound 4004)

To a solution of compound 4003 (23.5 g, 138 mmol) in acetic acid (300mL) was added bromine (22.7 g, 142 mmol). The mixture was heated atreflux for 3 h and concentrated in vacuum to afford the hydrobromidesalt of crude compound 4004 as a yellow solid. The product was useddirectly in next step without further purification. LCMS: m/z 169[M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=7.2 Hz, 3H), 4.28 (q,J=7.2 Hz, 2H), 8.85 (s, 2H), 12.19 (br, s, 2H).

Step 6d. Ethyl 2-chloropyrimidine-5-carboxylate (Compound 4005)

A mixture of crude compound 4004 and phosphoryl trichloride (300 mL) washeated at reflux for 3 h, cooled to room temperature and concentrated.The residue was cooled to room temperature and dissolved in ethylacetate (500 mL). The EtOAc solution was treated with ice water (300 mL)carefully, washed with ice-water and brine, dried over Na₂SO₄,evaporated, and purified by column chromatography (eluted withEtOAc/Hexane: 10%) to afford compound 4005 (14 g, 54%, two steps) as awhite solid. LCMS: m/z 187 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 1.42 (t,J=7.5 Hz, 3H), 4.48 (q, J=7.5 Hz, 2H), 9.15 (s, 2H).

Step 6e. Ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate (compound4006)

A mixture of tert-butyl piperazine-1-carboxylate (1.1 g, 5.9 mmol) and4005 (1 g, 5.4 mmol), Et₃N (1.1 g, 10.8 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temperature for 2 h. The reaction mixture was washedwith H₂O. The organic layer was concentrated. The residue was purifiedby chromatography eluting with Hexane/EtOAc=250:10, then 250:20 toafford the compound ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (900mg, 45.4%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.37 (t, 3H,J=6.8 Hz), 1.49 (s, 9H), 3.51 (t, 4H, J=4.8 Hz), 3.92 (t, 4H, J=5.2 Hz),4.35 (q, 2H, J=7.2 Hz), 8.85 (s, 2H).

A mixture of above product (500 mg, 1.49 mmol) and HCl/dioxane (10 mL)was stirred at room temperature for 2 h. The reaction mixture wasconcentrated. The residue was partitioned between EtOAc and saturatedaq. NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄and concentrated to afford the titled compound 4006 (370 mg, 88.2%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ 1.39 (t, 3H, J=6.8 Hz), 2.96 (t,4H, J=4.8 Hz), 3.95 (t, 4H, J=5.2 Hz), 4.36 (q, 2H, J=7.2 Hz), 8.86 (s,2H).

Step 6f.2-[4-(4-Carboxy-3-chloro-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylicacid methyl ester (compound 4007)

To a mixture of 4006 (1.04 g, 4.7 mmol) and DIPEA (4.0 g, 31.2 mmol) indicholoromethane (80 mL) was added compound 3003 (1.0 g, 3.9 mmol). Themixture solution was stirred at room temperature overnight. The reactionmixture was adjusted pH to 6˜7 with 2M HCl and extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate, evaporated in vacuo. The crudeproduct was purified by column chromatography (methane/dichloromethane:1/20) to afford compound 4007 as a white solid (520 mg, 30% yield).LCMS: m/z 455.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.27 (t, J=7.2 Hz,3H), 3.08 (br, 4H), 3.96 (br, 4H), 4.25 (q, J=7.2 Hz, 2H), 7.72 (dd,J=8.0 Hz, 1.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H),8.76 (s, 2H).

Step 6 g.2-{4-[2-Chloro-4-(4-chloro-3-pyridin-2-yl-phenylcarbamoyl)-benzenesulfonyl]-piperazin-1-yl}-pyrimidine-5-carboxylicacid methyl ester (compound 4008)

A mixture of 4007 (500 mg, 1.1 mmol), oxalyl chloride (1.59 g, 12.5mmol) and DMF (0.05 mL) in dichloromethane (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated and theresidue was dissolved in dichloromethane (15 mL). Compound 1-8 (278 mg,1.2 mmol) and DIPEA (325 mg, 2.5 mmol) were added. The resulting mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with water and extracted with dichloromethane. The combinedorganic layers were washed with water and brine, dried over anhydroussodium sulfate and evaporated in vacuo. The crude product was purifiedby column chromatography (methanol/dichloromethane: 1/20) to affordcompound 4008 as a white solid (180 mg, 25% yield). LCMS: m/z641.2[M+1]⁺. 1H NMR (400 MHz, DMSO-d₆): δ 1.28 (t, J=7.2 Hz, 3H), 3.11(br, 4H), 3.99 (br, 4H), 4.26 (q, J=7.2 Hz, 2H), 7.43-7.46 (m, 1H), 7.58(d, J=8.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.72 (dd, J=8.8 Hz, 2.8 Hz,1H), 7.83 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.88-7.91 (m, 2H), 7.93 (dd, J=8.0Hz, 2.0 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.78(s, 2H), 10.84 (s, 1H).

Step 6 h.2-{4-[2-Chloro-4-(4-chloro-3-pyridin-2-yl-phenylcarbamoyl)-benzenesulfonyl]-piperazin-1-yl}-pyrimidine-5-carboxylicacid hydroxyamide (compound 86)

A mixture of 4008 (180 mg, 0.3 mmol) and NH₂OH (15 mL, 1.79M) methanolicsolution was stirred at room temperature for 2.5 h. The reaction mixturewas adjusted pH to 5˜6 with 2M HCl and evaporated. The resulting mixturewas filtered. The crude product was purified by prep-HPLC to affordcompound 86 as a white solid (50 mg, 26% yield). M.p.: 158.7-159.3° C.LCMS: m/z 628.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.09 (br, 4H), 3.93(br, 4H), 7.43-7.46 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.69-7.73 (m, 2H),7.83 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.87-7.90 (m, 2H), 7.93 (dd, J=7.6 Hz,1.6 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 8.66 (s, 2H), 8.70 (d, J=4.0 Hz,1H), 9.02 (s, 1H), 10.84 (s, 1H), 11.09 (s, 1H).

Example 7:N-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenyl)-3-(7-(hydroxyamino)-7-oxoheptyloxy)benzamide(compound 111) Step 7a.3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)phenylacetate (compound 5001-111)

3-Acetoxybenzoic acid (2.6 g, 0.015 mol) was added to a mixture ofcompound 2-3 (3.5 g, 0.012 mol), HATU (6.9 g, 0.018 mol) and Et₃N (2.5mL, 0.018 mol) in dichloromethane (30 mL). The reaction mixture wasstirred at room temperature overnight. The mixture was quenched withwater and extracted with dichloromethane. The combined organic layerswere washed with water and brine, dried over anhydrous Na₂SO₄. The crudeproduct was purified by column chromatography (hexanes/ethyl acetate:1/1) to afford compound 5001-111 as a white solid (2.6 g, 49% yield).LCMS: m/z 449.2 [M+1]⁺.

Step 7b.N-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenyl)-3-hydroxybenzamide(compound 5002-111)

To a solution of compound 5001-111 (1.0 g, 0.002 mol) in MeOH (15 mL)was added a solution of NaOH (0.89 g, 0.02 mol) in H₂O (15 mL). Thereaction mixture was heated at reflux overnight. After cooling at icebath, the mixture was adjusted pH to 7˜8 with 1M HCl and extracted withethyl acetate. The combined organic layers were washed with water andbrine, dried over anhydrous Na₂SO₄, evaporated in vacuo to afford crudecompound 5002-111 as a yellow solid (0.81 g, 100% yield). LCMS: m/z407.2 [M+1]⁺.

Step 7c.Ethyl-7-(3-(4-chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)phenoxy)heptanoate(compound 5003-111)

To a mixture of compound 5002-111 (1.40 g, 0.0034 mol), ethyl7-hydroxyheptanoate (0.89 g, 0.0052 mol) and PPh₃ (1.8 g, 0.0069 mol) inanhydrous THF (20 mL) was added DIAD (1.39 g, 0.0069 mol) at 0° C. undernitrogen atmosphere. The resulting solution was heated at 65° C.overnight. After cooling to room temperature, the reaction mixture wasconcentrated in vacuo. The crude product was purified by columnchromatography (dichloromethane/ethyl acetate: 1:1) to afford compound5003-111 as a white solid (0.9 g, 47% yield). LCMS: m/z 563.3 [M+1]⁺.

Step 7d.N-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenyl)-3-(7-(hydroxyamino)-7-oxoheptyloxy)benzamide(Compound 111)

Compound 5003-111 (120 mg, 0.21 mmol) was taken into NH₂OH methanolicsolution (10 mL, 1.79 M). The mixture stirred at room temperature for 40min. The reaction mixture was adjusted pH to 8-9 with acetic acid andconcentrated in vacuo. The residue was purified by prep-HPLC to affordcompound 111 as a white solid (30 mg, 26% yield). M.p: 140˜142° C. LCMS:m/z 550.3 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 1.28-1.35 (m, 2H),1.40-1.56 (m, 4H), 1.72-1.76 (m, 2H), 1.96 (t, J=3.2 Hz, 2H), 2.93 (s,6H), 4.05 (t, J=6.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.16-7.18 (m, 1H),7.43-7.61 (m, 5H), 7.97 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.23 (s, 1H), 8.42(d, J=2.4 Hz, 1H), 10.36 (s, 1H), 10.47 (s, 1H), 12.23 (br, 1H).

Example 8:2-((3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (compound 263) Step 8a.1-Bromo-4-(bromomethyl)-2-chlorobenzene (compound 6002)

A mixture of 1-bromo-2-chloro-4-methylbenzene (5 g, 24 mmol), NBS (5.19g, 29 mmol), AIBN (0.39 g, 2.0 mmol) in CCl₄ (50 mL) was heated atreflux overnight. The hot reaction mixture was filtered and rinsed withCCl₄. The combined organic layer was washed with water and brine, driedover NaSO₄, evaporated in vacuo to afford compound 6002 as a white solid(5.6 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 4.39 (s, 2H), 7.14 (dd,J=8.0 Hz, 2.0 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H).

Step 8b. tert-Butyl 4-bromo-3-chlorobenzyl(methyl)carbamate (compound6003)

To a stirring solution of MeNHBoc in DMF (10 mL) cooled to 0° C. wasadded sodium hydride (590 mg, 24.6 mmol). The resulting mixture wasstirred for 10 min followed by the addition of a solution of 6002 (4.67g, 16.0 mmol) in DMF (5 mL). The reaction mixture was warmed to roomtemperature and stirred for 8 h. The reaction mixture was quenched withice water and extracted with ethyl acetate. The combined organic layerswere washed with water and brine, dried over anhydrous sodium sulfateand evaporated in vacuo. The crude product was purified by columnchromatography (ethyl acetate/hexanes: 1/10) to afford 6003 as a whitesolid (1.8 g, 34% yield). ¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 2.83(d, J=18.4 Hz, 3H), 4.35 (s, 2H), 6.99 (s, 1H), 7.32 (s, 1H), 7.56 (d,J=8.4 Hz, 1H).

Step 8c. tert-Butyl 3-chloro-4-formylbenzyl(methyl)carbamate (compound6004)

To a solution of 6003 (2.15 g, 6.4 mmol) in anhydrous THF (20 mL) wasadded n-BuLi (3.8 mL, 2.5 M, 9.5 mmol) dropwise at −78° C. The resultingmixture was continued to stir for 2 h followed by the addition ofN-formyl morpholine (884 mg, 7.7 mmol) at −78° C. The resulting mixturewas warmed to room temperature and stirred overnight. The reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried overanhydrous sodium sulfate and evaporated in vacuo. The crude product waspurified by column chromatography (ethyl acetate/hexanes: 1/10) toafford compound 6004 as a red oil (570 mg, 25% yield). LCMS: m/z 282.1[M−1]⁻. ¹H NMR (400 MHz, CDCl₃): δ 1.45, 1.50 (two single peaks, 9H),2.85, 2.90 (two single peaks, 3H), 4.46 (br, 2H), 7.23 (d, J=6.8 Hz,1H), 7.31 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 10.45 (s, 1H).

Step 8d. Ethyl2-((3-chloro-4-formylbenzyl)(methyl)amino)pyrimidine-5-carboxylate(compound 6005)

A mixture of 6004 (570 mg, 2.0 mmol) in TFA (10 mL) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated. The residuewas mixed with 4005 (560 mg, 3.0 mmol) and TEA (10 ml) and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas quenched with water and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄. Thecrude product was purified by column chromatography (ethylacetate/hexanes: 1/5) to afford compound 6005 as a yellow solid (425 mg,65% yield). LCMS: m/z 334.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.29(t, J=7.2 Hz, 3H), 3.22 (s, 3H), 4.27 (q, J=7.2 Hz, 2H), 5.02 (s, 2H),7.36 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.79, 8.86(two single peaks, 2H), 10.29 (s, 1H).

Step 8e.2-Chloro-4-(((5-(ethoxycarbonyl)pyrimidin-2-yl)(methyl)amino)methyl)benzcacid (compound 6006)

A mixture of compound 6005 (425 mg, 1.27 mmol), NaIO₄ (408 mg, 1.9mmol), RuCl₃ (40 mg, 0.2 mmol) in CH₃CN (15 mL) was stirred at roomtemperature for 16 h. The reaction mixture was quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith water and brine, dried over Na₂SO₄. The crude compound 6006 wasobtained as a white solid (188 mg) which used directly for the nextstep. LCMS: m/z 350.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t,J=7.2 Hz, 3H), 3.21 (s, 3H), 4.28 (q, J=7.2 Hz, 2H), 4.98 (s, 2H), 7.26(d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 8.80, 8.86 (twosingle peaks, 2H).

Step 8f.Ethyl2-((3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)(methyl)amino)pyrimidine-5-carboxylate (compound 6007)

A mixture of 6006 (118 mg, 0.3 mmol) in DMF (0.10 mL), thionyl chloride(2 mL, 27.5 mmol) was stirred at room temperature overnight. Thereaction mixture was concentrated and the residue was dissolved inanhydrous dichloromethane (5 mL) and cooled at ice bath. To the mixturewas added DIPEA (1.0 mL, 6.0 mmol) and compound 1-8 (83 mg, 0.4 mmol)and the resultuing mixture was warmed to room temperature and stirredovernight. The reaction was quenched with water and extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over NaSO₄. The crude product was purified by columnchromatography (ethyl acetate/dichloromethane: 5/1) to afford compound6007 as a white solid (100 mg 50% yield). LCMS: m/z 536.2 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H), 3.22 (s, 3H), 4.28 (q,J=7.2 Hz, 2H), 4.99 (s, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.43-7.45 (m, 2H),7.54-7.58 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.4 Hz,1H), 7.90-7.94 (m, 1H), 8.02 (d, J=2.8 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H),8.82-8.86 (m, 2H), 10.71 (s, 1H).

Step 8 g.2-((3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (compound 263)

Compound 6007 (100 mg, 0.2 mmol) was taken into NH₂OH methanolicsolution (10 mL, 1.79 M). The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was adjusted pH to 7˜8 withacetic acid and concentrated. The residue was triturated with water andfiltered to afford compound 263 as a white solid (60 mg, 60% yield).LCMS: m/z 523.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): 3.19 (s, 3H), 4.96(s, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.54-7.57 (m, 2H),7.67 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 2.8 Hz, 1H), 7.90-7.94 (m,1H), 8.01 (d, J=2.4 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.74 (s, 2H), 9.03(s, 1H), 10.75 (s, 1H), 11.21 (s, 1H).

Example 9: 2-(3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)-N-hydroxypyrimidine-5-carboxamide (compound 265) Step9a. Methyl 2-chloro-4-sulfamoylbenzoate (compound 7001)

Compound 3003 (200 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL)followed by the addition of saturated NH₃ methanolic solution (0.5 mL)at 0° C. After addition, the reaction mixture was warmed to roomtemperature and stirred for 5 min. After evaporation, the residue waspurified by column chromatography (hexanes/ethyl acetate: 3/1) to affordcompound 7001 as a white solid (160 mg, 86% yield). LCMS: m/z248.0[M−1]⁻. ¹H NMR (400 MHz, DMSO-d₆): δ 3.91 (s, 3H), 7.69 (s, 2H),7.88 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 8.02 (d, J=8.0Hz, 1H).

Step 9b. 4-(N-(tert-Butoxycarbonyl)sulfamoyl)-2-chlorobenzoic acid(compound 7002)

A mixture of 7001 (1.44 g, 5.8 mmol), Boc₂O (2.51 g, 11.5 mmol) and DMAP(71 mg) in dichloromethane (30 mL) was heated at reflux overnight. Aftercooling to room temperature, the mixture was quenched with water,extracted with ethyl acetate. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄. The crude product waspurified by column chromatography (hexanes/ethyl acetate: 2/1) to affordcompound methyl 4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-chlorobenzoate asa white solid (1.20 g, 60% yield). LCMS: m/z 350.2 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 1.32 (s, 9H), 3.91 (s, 3H), 7.94 (dd, J=8.0 Hz, 1.6 Hz,1H), 7.97 (d, J=1.6 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 12.03 (br, 1H).

A mixture of above product (1.22 g, 3.5 mmol), LiOH (1.46 g, 34.9 mmol)in THF/H₂O (10 mL/10 mL) was stirred at room temperature overnight.After evaporation, the mixture was adjusted to pH 1˜2 with 1M HCl andextracted with ethyl acetate. The combined organic layers were washedwith water and brine, evaporated in vacuo to afford compound 7002 as awhite solid (1.00 g, 85% yield). LCMS: m/z 334.0 [M−1]⁻. ¹H NMR (400MHz, DMSO-d₆): δ 1.32 (s, 1H), 7.90 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.94 (d,J=1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 11.99 (br, 1H).

Step 9c. tert-Butyl3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonylcarbamate (compound 7003)

A mixture of compound 7002 (328 mg, 1.0 mmol), 1-8 (100 mg, 0.5 mmol),HATU (559 mg, 1.5 mmol), DIPEA (253 mg, 2.0 mmol) in DMF (5 mL) wasstirred at room temperature overnight. The mixture was quenched withsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄. The crude product was purified by columnchromatography (dichloromethane/ethyl acetate: 2/1) to afford compound7003 as a white solid (270 mg, ˜100% yield). LCMS: m/z 522.2 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 1.36 (s, 9H), 7.44-7.47 (m, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.76 (dd, J=8.8 Hz, J=2.4 Hz,1H), 7.91-7.98 (m, 4H), 8.01 (d, J=2.4 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H),10.93 (s, 1H), 11.98 (br, 1H).

Step 9d.2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide(compound 7004)

A mixture of 7003 (270 mg, 0.5 mmol) in TFA (5 mL) was stirred at roomtemperature for 2 h. After evaporation, the mixture was quenched withsaturated NaHCO₃ and extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄,evaporated in vacuo to afford compound 7004 as a white solid (180 mg,84% yield). LCMS: m/z 422.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ7.43-7.47 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.64 (s, 2H), 7.69 (d, J=8.0Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.82-7.88 (m, 2H), 7.91-7.96(m, 2H), 8.01 (d, J=2.4 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 10.88 (s, 1H).

Step 9e. Ethyl2-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)pyrimidine-5-carboxylate (compound 7005)

A mixture of compound 7004 (460 mg, 1.1 mmo), 4005 (203 mg, 1.1 mmol),cesium carbonate (533 mg, 1.6 mmol), Xantphos (20 mg, 0.03 mmol),Pd₂(dba)₃ (20 mg, 0.02 mmol) in 1,4-dioxane (15 mL) was heated at 85° C.overnight. After cooling to room temperature, the reaction mixture wasquenched with water and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over anhydrousNa₂SO₄. The crude product was purified by column chromatography(dichloromethane/ethyl acetate: 2/1) to afford compound 7005 as a paleyellow solid (300 mg, 48% yield). LCMS: m/z 572.1 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H),7.43-7.46 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.67-7.73 (m, 2H), 7.84 (d,J=8.0 Hz, 1H), 7.90-7.94 (m, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.06 (dd,J=8.0 Hz, 1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.69-8.71 (m, 1H), 8.96(s, 2H), 9.05 (s, 1H).

Step 9f.2-(3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)-N-hydroxypyrimidine-5-carboxamide(compound 265)

Compound 7005 (300 mg, 0.5 mmol) was taken into NH₂OH methanolicsolution (10 mL, 1.79 M). The resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was adjusted pH to 7˜8 withacetic acid and concentrated. The residue was triturated with water andfiltered. The solid was suspended in dichloromethane and stirred at roomtemperature overnight and filtered. The collected solid was dried invacuo to afford compound 265 as a white solid (60 mg, 21% yield). M.p:215˜220° C.

LCMS: m/z 559.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 7.42-7.46 (m, 1H),7.56 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),7.73 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.90-7.94 (m,2H), 8.01 (d, J=2.4 Hz, 1H), 8.53 (s, 2H), 8.70 (d, J=4.4 Hz, 1H), 8.93(s, 1H), 10.79 (s, 1H), 10.96 (br, 1H).

Example 10:(E)-2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-(3-(hydroxyamino)-3-oxoprop-1-enyl)phenyl)sulfamoyl)benzamide(compound 254) Step 10a. 2-(3-Nitrophenyl)-1,3-dioxolane (compound 8002)

A mixture of 3-nitrobenzaldehyde (7.0 g, 46.3 mmol), ethylene glycol(14.4 g, 231.5 mmol), p-toluenesulfonic acid (0.79 g, 4.6 mmol) intoluene (80 mL) was heated at reflux overnight. After cooling to roomtemperature, the reaction mixture was quenched with aqueous sodiumbicarbonate and extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over anhydrous Na₂SO₄ andevaporated in vacuo to afford compound 8002 as a yellow oil (8.6 g,95%). ¹H NMR (400 MHz, CDCl₃): δ 4.05-4.11 (m, 2H), 4.12-4.16 (m, 2H),5.89 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 8.21-8.24(m, 1H), 8.35-8.36 (m, 1H).

Step 10b. 3-(1,3-Dioxolan-2-yl)aniline (compound 8003)

A mixture of 8002 (215 mg, 1.1 mmol), Pd/C (100 mg, 50%) in ethanol (10mL) was stirred under hydrogen at room temperature overnight. Themixture was filtered and the filtrate was evaporated in vacuo. The crudeproduct was purified by column chromatography (hexanes/ethyl acetate:8/1) to afford compound 8003 as a yellow solid (100 mg, 55%). LCMS: m/z166.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.86-4.03 (m, 4H), 5.10 (s,1H), 5.55 (s, 1H), 6.54 (d, J=7.6 Hz, 2H), 6.63 (s, 1H), 6.99 (t, J=7.6Hz, 1H).

Step 10c. Methyl4-(N-(3-(1,3-dioxolan-2-yl)phenyl)sulfamoyl)-2-chlorobenzoate (compound8004)

A mixture of 8003 (1.12 g, 6.8 mmol), 3003 (2.21 g, 8.2 mmol), anhydrouspyridine (1.3 g, 16.4 mmol) in anhydrous CH₂Cl₂ (10 mL) was heated atreflux for 30 min. The mixture was quenched with water and adjusted pHto 2-3 with HCl (1.0M). The resulting mixture was extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate and evaporated in vacuo. The crudeproduct was purified by column chromatography (hexanes/ethyl acetate:10/1) to afford compound 8004 as a yellow oil (2.16 g, 80%). LCMS: m/z398.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.87 (s, 3H), 3.91-3.93 (m,2H), 3.94-3.96 (m, 2H), 5.66 (s, 1H), 7.10-7.17 (m, 3H), 7.29 (t, J=8Hz, 1H). 7.77 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.96(d, J=8.0 Hz, 1H), 10.58 (s, 1H).

Step 10d. 4-(N-(3-(1,3-Dioxolan-2-yl)phenyl)sulfamoyl)-2-chlorobenzoicacid (compound 8005)

LiOH (264 mg, 6.25 mmol) was added into a solution of 8004 (500 mg, 1.25mmol) in THF/H₂O (5 mL/5 mL). The mixture was stirred at roomtemperature overnight. The mixture was quenched with HCl (1 M) andadjusted pH to 1-2. The resulting mixture was extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate and evaporated in vacuo to affordcompound 8005 as a red solid (450 mg, 94%). LCMS: m/z 384.1 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆): 3.91-3.93 (m, 2H), 3.95-3.97 (m, 2H), 5.67 (s,1H), 7.11-7.18 (m, 3H), 7.30 (t, J=8.0 Hz, 1H). 7.74 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 10.57 (s, 1H).

Step 10e.4-(N-(3-(1,3-Dioxolan-2-yl)phenyl)sulfamoyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide(compound 8006)

A mixture of 8005 (284 mg, 0.74 mmol), 1-8 (100 mg, 0.49 mmol), HATU(373 mg, 0.98 mmol), DIPEA (159 mg, 1.23 mmol) in anhydrous DMF (5 mL)was stirred overnight. The mixture was quenched with water and extractedwith ethyl acetate. The combined organic layers were washed with waterand brine, dried over anhydrous sodium sulfate and evaporated in vacuo.The crude product was purified by column chromatography (hexanes/ethylacetate: 5/1) to afford compound 8006 as a yellow solid (248 g, 88%).LCMS: m/z 570.2 [M+1]⁺.

Step 10f.2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-formylphenyl)sulfamoyl)benzamide (compound 8007)

A mixture of 8006 (120 mg, 0.18 mmol) and HCl (5 mL) in THF/H₂O (5 mL/5mL) was refluxed for 1 h. The mixture was quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith water and brine until pH 7. The organic layer was dried overanhydrous Na₂SO₄ and evaporated in vacuo. The crude product was purifiedby column chromatography (hexanes/ethyl acetate: 5/1) to afford compound8007 as a yellow solid (90 mg, 82%). LCMS: m/z 526.2 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): 7.42-7.50 (m, 2H), 7.53-7.57 (m, 2H), 7.60-7.72 (m, 5H),7.81-7.86 (m, 2H), 7.91 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.94 (br, 1H), 7.96(d, J=2.4 Hz, 1H), 8.70 (d, J=4.8 Hz, 2H), 9.94 (s, 1H), 10.84 (s, 1H),10.91 (s, 1H).

Step 10 g. (E)-methyl3-(3-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)phenyl)acrylate (compound 8008)

A mixture of 8007 (110 mg, 0.21 mmol), methyl-(dimethoxyphosphoryl)acetate (58 mg, 0.32 mmol) and sodium methoxide (34 mg, 0.63 mmol) inanhydrous DMF was stirred at room temperature overnight. The mixture wasquenched with HCl (1 M) and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over anhydroussodium sulfate and evaporated in vacuo. The crude product was purifiedby column chromatography (CH₂Cl₂/ethyl acetate: 6/1) to afford compound8008 as a yellow solid (45 mg, 37%). LCMS: m/z 582.2[M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): 3.72 (s, 3H), 6.52 (d, J=16.4 Hz, 1H), 7.19 (d, J=8.4 Hz,1H), 7.34 (t, J=7.2 Hz, 1H), 7.41-7.49 (m, 3H), 7.55-7.61 (m, 2H),7.66-7.72 (m, 2H), 7.80-7.86 (m, 2H), 7.90 (dd, J=8.0 Hz, 2.0 Hz, 1H),7.93-7.96 (m, 2H), 8.70 (d, J=4.4 Hz, 1H), 10.71 (s, 1H), 10.83 (s, 1H).

Step 10 h.(E)-2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-(3-(hydroxyamino)-3-oxoprop-1-enyl)phenyl)sulfamoyl)benzamide(compound 254)

Compound 8008 (45 mg, 0.077 mmol) was taken into NH₂OH methanolicsolution (10 mL, 1.79 M). The resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was adjusted pH to 7˜8 withacetic acid and concentrated. The residue was triturated with water andfiltered. The collected solid was purified with prep-HPLC to affordcompound 254 as an off-white solid (13 mg, 31% yield). M.p.: 217˜221° C.LCMS: m/z 583.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): 6.41 (d, J=15.6 Hz,1H), 7.12 (d, J=7.6, 1H), 7.18 (s, 1H), 7.25-7.38 (m, 4H), 7.42-7.45 (m,1H), 7.56 (d, J=8.8 Hz, 1H), 7.66-7.72 (m, 2H), 7.80-7.90 (m, 1H),7.90-7.97 (m, 3H), 8.70 (d, J=4.4 Hz, 1H), 10.71 (s, 1H), 10.80 (br,1H), 10.84 (s, 1H).

Example 11: 2-(4-((3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(compound 90) Step 11a. tert-Butyl4-((3-chloro-4-(methoxycarbonyl)phenylsulfonamido)methyl)piperidine-1-carboxylate (compound 9001)

To a mixture of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (570mg, 2.6 mmol) and 3003 (600 mg, 2.2 mmol) in dichloromethane (10 mL) wasadded triethylamine (0.6 mL, 4.4 mmol). The mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate and washed with 1N HCl. The ethyl acetate layer was concentratedin vacuo and purified by column chromatography (hexanes:ethylacetate=5:1) to give compound 9001 as a white solid (610 mg, 62% yield).LCMS: m/z 445.1 [M−1]⁻. ¹H NMR (400 MHz, DMSO-d6): δ 0.87-0.98 (m, 2H),1.37 (s, 9H), 1.49-1.60 (m, 3H), 2.62-2.70 (m, 4H), 3.86 (br, 2H), 3.90(s, 3H), 7.84 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.94(t, J=5.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H).

Step 11b.4-(N-((1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl)sulfamoyl)-2-chlorobenzoicacid (compound 9002)

To the solution of 9001 (610 mg, 1.4 mmol) in THF (16 mL) and H₂O (8 mL)was added LiOH (286 mg, 12.0 mmol). The mixture was stirred at roomtemperature for 3 h. The reaction mixture was acidified to pH=5 with 1NHCl and extracted with ethyl acetate. The ethyl acetate layer was driedover Na₂SO₄, filtered and concentrated in vacuo to give compound 9002 asa white solid (530 mg, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ0.89-0.98 (m, 2H), 1.37 (s, 9H), 1.52-1.61 (m, 3H), 2.65-2.69 (m, 4H),3.89 (d, J=12.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.91 (t,J=6.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H).

Step 11c. tert-Butyl4-((3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)methyl)piperidine-1-carboxylate (compound 9003)

To a mixture of 9002 (530 mg, 1.2 mmol) and 1-8 (200 mg, 1.0 mmol) inDMF (2.0 mL) was added DIPEA (300 mg, 2.3 mmol) followed by HATU (733mg, 1.9 mmol). The resulting solution was stirred at room temperatureovernight. The reaction mixture was poured into water and extracted withethyl acetate. The organic phase was washed with NH₄Cl solution, waterand brine, dried over Na₂SO₄ and concentration in vacuo. The crude solidwas purified by column chromatography eluted with ethylacetate:dichloromethane=3:1 to give compound 9003 as a yellow solid (120mg, 16%).

LCMS: m/z 619.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 0.90-1.09 (m, 2H),1.38 (s, 9H), 1.52-1.63 (m, 3H), 2.66-2.69 (m, 4H), 3.90 (d, J=10.8 Hz,2H), 7.40-7.47 (m, 1H), 7.58-7.60 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.75(dd, J=8.8 Hz, 2.0 Hz, 1H), 7.84 (s, 2H), 7.90-7.92 (m, 3H), 8.01 (d,J=2.0 Hz, 1H), 8.65, 8.70 (2 doublet peaks, J=5.2 Hz, 1H), 10.87 (s,1H).

Step 11d.2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(piperidin-4-ylmethyl)sulfamoyl)benzamide(compound 9004)

To the solution of 9003 (120 mg, 0.2 mmol) in dichloromethane (1 mL) wasadded TFA (1 mL). The mixture was stirred at room temperature for 1 h.The reaction solution was concentrated. The residue was dissolved withethyl acetate and washed with NaHCO₃ solution. The ethyl acetate layerwas dried over Na₂SO₄, filtered and concentrated in vacuo to givecompound 9004 as a yellow solid (100 mg, 99% yield).

LCMS: m/z 519.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 1.10-1.15 (m, 2H),1.57 (br, 1H), 1.69 (d, J=13.2 Hz, 2H), 2.60-2.69 (m, 4H), 3.10 (d,J=12.0 Hz, 2H), 7.43 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.69 (d,J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.85 (s, 2H), 7.91-7.94 (m, 2H),8.01 (s, 1H), 8.71 (d, J=4.4 Hz, 1H), 10.88 (s, 1H).

Step 11e. Ethyl2-(4-((3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)methyl)piperidin-1-yl)pyrimidine-5-carboxylate (compound9005)

To the solution of 9004 (100 mg, 0.2 mmol) and Et₃N (0.2 mL, 1.4 mmol)in DCM (2 mL) was added 4005 (39 mg, 0.2 mmol). The resulting mixturewas stirred at room temperature for 1 h. The reaction mixture wasdiluted with ethyl acetate and washed with 1N HCl. The ethyl acetatelayer was dried over Na₂SO₄, filtered and concentrated to give compound9005 as a yellow solid (135 mg, 96% yield). LCMS: m/z 669.3 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d6): δ 1.10-1.18 (m, 2H), 1.29 (t, J=7.2 Hz, 3H),1.76 (d, J=6.0 Hz, 2H), 2.68-2.72 (m, 2H), 2.94-3.00 (m, 2H), 4.27 (q,J=6.8 Hz, 2H), 4.72 (d, J=12.8 Hz, 2H), 7.45 (t, J=6.0 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.86 (s,2H), 7.92-8.01 (m, 3H), 8.71 (d, J=4.8 Hz, 1H), 8.77 (s, 2H), 9.28 (br,1H), 10.89 (s, 1H).

Step 11f. 2-(4-((3-Chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(compound 90)

Compound 9005 (135 mg, 0.2 mmol) was taken into NH₂OH methanolicsolution (1.79M, 10 mL). The resulting mixture was stirred in sealedtube at room temperature for 3 h. TLC showed reaction complete. Aceticacid was added to adjust pH to 6˜7 followed by the addition ofice-water. The reaction mixture was filtered, washed with water. Thecrude product was purified by prepared HPLC to afford compound 90 as awhite solid (30 mg, 22% yield). M.p.: 172-173° C. LCMS: m/z 656.2[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 1.04-1.07 (m, 2H), 1.73-1.76 (m,3H), 2.70-2.72 (m, 2H), 2.89-2.95 (m, 2H), 4.69 (d, J=12.8 Hz, 2H), 7.45(t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.75(d, J=8.4 Hz, 1H), 7.86 (s, 2H), 7.91-7.95 (m, 2H), 8.02 (s, 1H), 8.65(s, 2H), 8.71 (d, J=4.4 Hz, 1H), 8.99 (br, 1H), 10.88 (s, 1H), 10.99(br, 1H).

Example 12:2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide(compound 266) Step 12a.2-Chloro-4-(N-(2-(4-(ethoxycarbonyl)phenoxy)ethyl)sulfamoyl)benzoic acid(compound 1001)

To a mixture of ethyl 4-(2-aminoethoxy)benzoate (330 mg, 1.6 mmol) and3003 (400 mg, 1.6 mmol) in dichloromethane (10 mL) was addedtriethylamine (0.6 mL, 4.4 mmol). The mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate and washed with 1N HCl. The ethyl acetate layer was concentratedin vacuo and purified by column chromatography(dichloromethane:MeOH=50:1) to give compound 1001 as a yellow solid (270mg, 40% yield). LCMS: m/z 428.0 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ1.30 (t, J=7.2 Hz, 3H), 3.20-3.22 (m, 2H), 4.04 (t, J=4.8 Hz, 2H), 4.27(q, J=7.2 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.71(d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 8.12 (br, 1H).

Step 12b. Ethyl4-(2-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenylsulfonamido)ethoxy)benzoate (compound 1002)

To a mixture of compound 1001 (270 mg, 0.6 mmol) and 1-8 (108 mg, 0.5mmol) in DMF (2.0 mL) was added DIPEA (164 mg, 1.3 mmol) followed byHATU (289 mg, 0.8 mmol). The resulting solution was stirred overnight atroom temperature. The reaction mixture was poured into water andextracted with ethyl acetate. The organic phase was washed with 1N HClsolution, water, brine and dried over Na₂SO₄. The crude solid waspurified by column chromatography eluted with dichloromethane/MeOH=100/1to give compound 1002 as a yellow solid (130 mg, 33%). LCMS: m/z 614.2[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 1.28 (t, J=6.8 Hz, 3H), 3.24-3.26(m, 2H), 4.06-4.09 (m, 2H), 4.25 (q, J=6.8 Hz, 2H), 6.89 (d, J=8.4 Hz,2H), 7.43-7.47 (m, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H),7.80-7.95 (m, 7H), 8.01 (s, 1H), 8.24-8.27 (m, 1H), 8.70-8.72 (d, J=4.0Hz, 1H), 10.86 (s, 1H).

Step 12c.2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide(compound 266)

Compound 1002 (130 mg, 0.2 mmol) was taken into NH₂OH methanolicsolution (1.79M, 10 mL). The resulting mixture was stirred in sealedtube at room temperature for 3 h. TLC showed reaction complete. 1N HClwas added to adjust pH to 6˜7 followed by the addition of ice-water. Thereaction mixture was filtered, washed with water. The crude product waspurified by prep-HPLC to afford compound 266 as a yellow solid (41 mg,32% yield). mp: 138-139° C. LCMS: m/z 601.2 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d6): δ 3.23 (t, J=4.0 Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 6.92 (d,J=8.4 Hz, 2H), 7.45 (t, J=6.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.68-7.76(m, 4H), 7.86-7.96 (m, 4H), 8.02 (s, 1H), 8.19 (d, J=4.0 Hz, 1H), 8.71(d, J=4.4 Hz, 1H), 8.89 (br, 1H), 10.88 (s, 1H), 11.05 (s, 1H).

Example 13:2-(4-((5-(3-(1H-Benzo[d]imidazol-2-yl)-4-chlorophenylcarbamoyl)-6-methylpyridin-2-ylamino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(compound 91) Step 13a. 6-Bromo-2-methylnicotinaldehyde (compound 1102)

To a stirred solution of 3,6-dibromo-2-methylpyridine (2.0 g, 8.0 mmol)in dry THF (20 mL) was added n-BuLi (1.6M, 6.0 mL) dropwise at −78° C.When the addition was complete the reaction was continued for 1 h.Dichloromethane (642.4 mg, 8.8 mmol) was added at −78° C. and continuedto stir for 1 h. The reaction was allowed to warm to room temperaturefollowed by addition of HCl (1M, 10 mL). The mixture was extracted withethyl acetate. The organic layer was washed with brine and concentrated.The crude product was purified by column chromatography eluted withdichloromethane/methanol (30:1) to afford compound 1102 as a white solid(1.4 g, 90%).

Step 13b. 6-Bromo-2-methylnicotinic acid (compound 1103)

To a stirred solution of compound 1102 (1.4 g, 6.7 mmol) in acetone (20mL) was added Jones reagent (2.67M, 5.2 ml) at 0° C. The reactionmixture was warmed to room temperature and stirred for 30 min. SaturatedNaHCO₃ solution was added to adjust pH=5-6. The mixture was extractedwith ethyl acetate. The organic layer was washed with brine andconcentrated. The crude product was purified by column chromatographyeluted with ethyl acetate/hexanes (1:8) to afford compound 1103 as awhite solid (1.0 g, 66%). ¹H NMR (400 MHz, CDCl₃): δ 2.87 (s, 3H), 7.46(d, J=8.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H).

Step 13c.N-(3-(1H-benzo[d]imidazol-2-yl)-4-chlorophenyl)-6-bromo-2-methylnicotinamide(compound 1104)

Compound 1103 (1.0 g, 4.6 mmol) was added to a mixture of compound 2-3(1.2 g, 4.6 mmol), HATU (3.5 g, 5.5 mmol) and Et₃N (19 mL, 13.8 mmol) indichloromethane (30 mL). The reaction mixture was stirred at roomtemperature overnight. The mixture was quenched with water, extractedwith dichloromethane, concentrated. The crude product was purified bycolumn chromatography eluted with hexanes/ethyl acetate (1:1) to affordcompound 1104 as a white solid (1.0 g, 50%). LCMS: m/z 443.1[M+1]⁺.

Step 13d. tert-Butyl4-((5-(3-(1H-benzo[d]imidazol-2-yl)-4-chlorophenylcarbamoyl)-6-methylpyridin-2-ylamino)methyl)piperidine-1-carboxylate (compound 1105)

To a stirred solution of compound 1104 (500 mg, 1.13 mmol) in i-PiOH (10mL) was added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (930mg, 4.4 mmol) and K₂CO₃ (1.2 g, 8.7 mmol). The mixture was stirringunder 100° C. for 48 h. The mixture was quenched with water andextracted with dichloromethane. The crude product was purified by columnchromatography eluted with hexane/ethyl acetate (1:1) to afford compound1105 as a yellow solid (250 mg, 38% yield). LCMS: m/z 575.4[M+1]⁺¹H NMR(400 MHz, DMSO-d6): δ 1.06-1.12 (m, 2H), 1.45 (s, 9H), 1.73-1.76 (m,3H), 2.50 (s, 3H), 2.73-2.75 (m, 2H), 3.25 (s, 2H), 3.98-4.02 (m, 2H),6.43 (d, J=8.8 Hz, 1H), 7.02-7.05 (m, 1H), 7.25-7.34 (m, 2H), 7.63-7.66(m, 3H), 7.76 (d, J=7.6 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 8.41 (s, 1H),10.28 (s, 1H), 12.72 (s, 1H).

Step 13e. Methyl2-(4-((5-(3-(1H-benzo[d]imidazol-2-yl)-4-chlorophenylcarbamoyl)-6-methylpyridin-2-ylamino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate(compound 1106)

To a stirred solution of compound 1105 (70 mg, 0.12 mmol) indichloromethane was added TFA (3 mL). The mixture was stirred for 30min. The reaction solution was concentrated and the residue wasdissolved in dichloromethane (10 mL). To the solution was added 4005 (31mg, 0.14 mmol) and Et₃N (1 mL). The resulting mixture was stirred atroom temperature for 30 min and concentrated. The residue was purifiedby column chromatography eluted with hexanes/ethyl acetate (1:1) toafford compound 1106 as a yellow solid (70 mg, 94%). LCMS: m/z 611.3[M+1]⁺¹H NMR (400 MHz, DMSO-d6): δ 1.08-1.14 (m, 2H), 1.72-2.02 (m, 4H),2.45 (s, 3H), 2.94-3.05 (m, 3H), 3.80 (s, 3H), 4.77 (d, J=13.2 Hz, 2H),6.39 (d, J=8.8 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 7.23-7.27 (m, 2H),7.58-7.60 (m, 2H), 7.71 (d, J=7.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 2H), 8.35(s, 1H), 8.77 (s, 2H), 10.23 (s, 1H), 12.69 (s, 1H).

Step 13f.2-(4-((5-(3-(1H-Benzo[d]imidazol-2-yl)-4-chlorophenylcarbamoyl)-6-methylpyridin-2-ylamino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(compound 91)

Compound 1106 (70 mg, 0.11 mmol) was taken into NH₂OH methanolicsolution (10 mL, 1.79 M). The mixture was stirred at room temperaturefor 40 min. The reaction mixture was adjusted pH to 8-9 with acetic acidand concentrated. The residue was purified by HPLC to afford the titledcompound 91 as a white solid (37 mg, 53%).

M.p.: 194-196° C. LCMS: m/z 612.3[M+1]⁺¹H NMR (400 MHz, DMSO-d6): δ1.13-1.18 (m, 2H), 1.78-2.00 (m, 3H), 2.45 (s, 3H), 2.91-2.98 (m, 2H),3.22 (s, 2H), 4.73 (d, J=12.4 Hz, 2H), 6.38 (d, J=8.4 Hz, 1H), 7.00-7.02(m, 1H), 7.24-7.26 (m, 2H), 7.57-7.60 (m, 3H), 7.69-7.71 (d, J=7.2 Hz,1H), 7.86 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.65 (s, 2H), 8.97 (br, 1H),10.23 (s, 1H), 10.98 (br, 1H), 12.68 (s, 1H).

Example 14:2-(3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzylamino)-N-hydroxypyrimidine-5-carboxamide(compound 258) Step 14a. Methyl 3-(hydroxymethyl)-5-methoxybenzoate(compound 1202)

To a stirred solution of dimethyl 5-methoxyisophthalate (1.0 g, 4.5mmol) in THF (10 mL) was added DIBAL-H (6.6 mL, 6.6 mmol). The reactionmixture was stirred for overnight at room temperature. The reactionmixture was diluted with ethyl acetate and washed with water and brine.The organic phase was dried over Na₂SO₄ and concentrated. The crudeproduct was purified by column chromatography eluted with hexanes/EA(2:1) to afford compound 1202 as a yellow solid (600 mg, 68% yield).

LCMS: m/z 197.1[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 3.80 (s, 3H), 3.85(s, 3H), 4.53 (d, J=6.0 Hz, 2H), 5.35 (t, J=5.8 Hz, 1H), 7.15 (s, 1H),7.31 (s, 1H), 7.54 (s, 1H).

Step 14b. Methyl 3-(bromomethyl)-5-methoxybenzoate (compound 1203)

To a stirred solution of compound 1202 (800 mg, 4.0 mmol) indichloromethane (10 mL) was added PBr₃ (0.4 mL, 4.3 mmol). The reactionmixture was stirred for 1 h at room temperature. The reaction wasdiluted with ethyl acetate and washed with water and brine. The organicphase was dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography eluted with hexanes/ethyl acetate(5:1) to obtain compound 1203 as a yellow oil. (640 mg, 61% yield). ¹HNMR (400 MHz, CDCl₃): δ 3.85 (s, 3H), 3.92 (s, 3H), 7.12 (br, 1H), 7.49(br, 1H), 7.65 (br, 1H).

Step 14c. Methyl 3-(azidomethyl)-5-methoxybenzoate (compound 1204)

To a stirred solution of compound 1203 (640 mg, 2.5 mmol) in DMF (5 mL)was added NaN₃ (1.1 g 16.9 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction solution was diluted with ethylacetate and washed with water and brine. The organic phase was driedover Na₂SO₄ and concentrated. The crude product was purified by columnchromatography eluted with hexanes/ethyl acetate (5:1) to affordcompound 1204 as a yellow oil (500 mg, 91% yield). LCMS: m/z263.2[M+1+41]⁺.

Step 14d. Methyl 3-(aminomethyl)-5-methoxybenzoate (compound 1205)

To a stirred solution of compound 1204 (500 mg, 2.3 mmol) in THF (10 mL)was added PPh₃ (650 mg, 2.5 mmol) and stirred for 30 min. Water (100 mg,5.5 mmol) was added. The mixture was warmed to 60° C. and stirred for 2h. The reaction mixture was diluted with ethyl acetate and washed withwater and brine. The organic phase was dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyeluted with dichloromethane/MeOH (50:1) to afford compound 1205 as ayellow oil (300 mg, 68% yield). LCMS: m/z 196.1[M+1]⁺.

Step 14e. 3-(Aminomethyl)-5-methoxybenzoic acid (compound 1206)

Compound 1205 (300 mg, 1.5 mmol) was added to a mixture of LiOH (180 mg,7.5 mmol) in EtOH (2 mL) and H₂O (2 mL). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was adjustedpH to 6 with 2N HCl. The mixture was concentrated and directly used tonext step without further purification.

Step 14f.3-Methoxy-5-((5-(methoxycarbonyl)pyrimidin-2-ylamino)methyl)benzoic acid(compound 1207)

To a stirred solution of 1206 (200 mg, 1.0 mmol) and Et₃N (300 mg, 3.0mmol) in dichloromethane (5 mL) was added 4005 (176 mg, 1.0 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionsolution was diluted with ethyl acetate and washed with water and brine.The organic phase was dried over Na₂SO₄, then concentrated. The crudeproduct was purified by column chromatography eluted withdichloromethane/MeOH (50:1) to afford compound 1207 as a yellow solid(110 mg, 31% yield). LCMS: m/z 318.2[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ3.78 (s, 3H), 3.79 (s, 3H), 4.60 (d, J=6.4 Hz, 2H), 7.13 (s, 1H), 7.31(s, 1H), 7.49 (s, 1H), 8.67 (t, J=6.0 Hz, 1H), 8.75 (s, 2H).

Step 14 g. Methyl2-(3-(4-chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzylamino)pyrimidine-5-carboxylate (compound 1208)

To a stirred solution of compound 1207 (110 mg, 0.3 mmol), 2-3 (90 mg,0.3 mmol) and DIPEA (90 mg, 0.7 mmol) in DMF was added HATU (160 mg, 0.4mmol). The reaction mixture was stirred at room temperature overnight.The reaction mixture was diluted with ethyl acetate and washed withwater and brine. The organic phase was dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyeluted with hexanes/ethyl acetate (1:1) to afford compound 1208 as ayellow solid (60 mg, 30% yield). LCMS: m/z 586.3[M+1]⁺.

Step 14 h.2-(3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzylamino)-N-hydroxypyrimidine-5-carboxamide(compound 258)

Compound 1208 (70 mg, 0.1 mmol) was taken into NH₂OH methanolic solution(10 mL, 1.79 M). The mixture was stirred at room temperature for 40 min.The reaction mixture was adjusted pH to 8-9 with acetic acid andconcentrated. The residue was purified by prep-HPLC to afford the titledcompound 258 as a yellow solid (35 mg, 50%). M.p.: 158-159° C. LCMS: m/z587.3[M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 2.93 (s, 6H), 3.82 (s, 3H),4.60 (d, J=6.0 Hz, 2H), 6.78-6.97 (m, 2H), 7.10 (s, 1H), 7.41 (s, 1H),7.49-7.52 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.8 Hz, 1H),8.30 (t, J=6.2 Hz, 1H), 8.37 (br, 1H), 8.61 (s, 2H), 8.94 (br, 1H),10.42 (s, 1H), 10.98 (br, 1H), 12.17, 12.30 (two single peaks, 1H).

Example 15:2-((3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(compound 259) Step 15a. Methyl3-methoxy-5-((methylamino)methyl)benzoate (compound 1301)

To a solution of 1203 (150 mg, 0.6 mmol) in DMF (3 mL) was addedmethylamine methanol solution (2.5 mL). The reaction mixture was stirredat room temperature for 10 min. Water (10 mL) was added to the reactionmixture and the resulting reaction mixture was extracted with ethylacetate (10 mL×2). The combined organic layers were washed with water.The organic phase was dried over Na₂SO₄, filtered and evaporated to giveproduct 1301 as light yellow oil (100 mg, 83%). LCMS: m/z 210.1 [M+1]⁺.¹H NMR (400 MHz, CDCl₃): δ 2.45 (s, 3H), 3.77 (s, 2H), 3.85 (s, 3H),3.92 (s, 3H), 7.10 (s, 1H), 7.45 (s, 1H), 7.59 (s, 1H).

Step 15b. Methyl3-((tert-butoxycarbonyl(methyl)amino)methyl)-5-methoxybenzoate (compound1302)

(Boc)₂O (154 mg, 0.7 mmol), NEt₃ (101 mg, 1.0 mmol) and DMAP (6 mg, 0.05mmol) were added to a solution of compound 1301 (100 mg, 0.5 mmol) inanhydrous dichloromethane (10 mL). The reaction mixture was stirred atroom temperature for 2 h until TLC indicated that compound 1301 had beenconsumed. The reaction mixture was concentrated and the residue waspurified by column chromatography eluted with CH₂Cl₂: MeOH (10:1) toafford the titled compound 1302 as light yellow oil (110 mg, 75%).

Step 15c. 3-((tert-Butoxycarbonyl(methyl)amino)methyl)-5-methoxybenzoicacid (compound 1303)

NaOH aqueous solution (4.0M, 10 mL) was added to a solution of compound1302 (160 mg, 0.5 mmol) in methanol (5 mL). The solution was stirred atroom temperature for 2 h. The reaction mixture was acidified to pH 3˜4with conc. HCl solution and extracted with ethyl acetate (10 mL×2) anddried over Na₂SO₄. The title compound 1303 was obtained as a yellowsolid after concentration (100 mg, 66%). ¹H NMR (400 MHz, CDCl₃): δ 1.42(s, 9H), 2.78 (s, 3H), 3.78 (s, 3H), 4.37 (s, 2H), 6.96 (s, 1H), 7.44(s, 1H), 7.50 (s, 1H).

Step 15d. tert-Butyl3-(4-chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl(methyl)carbamate (compound 1304)

Compound 2-3 (97 mg, 0.3 mmol) was added to a solution of compound 1303(100 mg, 0.3 mmol), HATU (137 mg, 0.4 mmol) and DIPEA (78 mg, 0.6 mmol)in DMF (4 mL). The reaction mixture was stirred at room temperatureovernight. The mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL×2). The organic layer was washed with water anddried over Na₂SO₄. The titled compound 1304 was obtained as yellow solidafter concentration (150 mg, 89%). LCMS: m/z 564.3 [M+1]⁺.

Step 15e.N-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenyl)-3-methoxy-5-((methylamino)methyl)benzamide(compound 1305)

Compound 1304 (150 mg) was dissolved in trifluoroacetic acid (10 mL).The reaction mixture was stirred at room temperature for 1 h. Thereaction was then concentrated to remove most trifluoroacetic acid. Theresidue was adjusted to pH 7˜8 with saturated aqueous NaHCO₃ solutionand extracted with ethyl acetate. The organic layer was washed withbrine and dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography eluted with CH₂Cl₂: MeOH (20:1) toafford the titled compound 1305 as a light yellow solid (50 mg, 40%). ¹HNMR (400 MHz, CDCl₃): δ 2.69 (s, 3H), 3.00 (s, 6H), 3.76 (s, 3H), 3.91(s, 2H), 6.85 (s, 2H), 6.90 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.33˜7.38 (m,2H), 7.52 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 8.06˜8.11 (m, 2H), 9.03 (br,1H).

Step 15f. Ethyl2-((3-(4-chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)pyrimidine-5-carboxylate(compound 1306)

To a solution of compound 1305 (50 mg, 0.1 mmol) in dichloromethane wasadded compound 4005 (19 mg, 0.1 mmol) and NEt₃ (30 mg, 0.3 mmol). Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was washed with water and concentrated to afford the titlecompound 1306 (90 mg). LCMS: 614.3 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ1.36 (t, J=7.2 Hz, 3H), 3.00 (s, 6H), 3.24 (s, 3H), 3.85 (s, 3H), 4.34(q, J=7.2 Hz, 2H), 4.99 (s, 2H), 6.87˜6.92 (m, 2H), 6.98 (s, 1H), 7.32(s, 2H), 7.47 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 8.23˜8.24 (m,3H), 8.90 (s, 2H).

Step 15 g.2-((3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(compound 259)

Compound 1306 (90 mg, 0.1 mmol) was dissolved in NH₂OH methanol solution(20 mL, 1.79M). The mixture was stirred at room temperature for 1 h. Thereaction mixture was adjusted pH to 8-9 with 2N HCl and evaporated invacuo. The residue was triturated with water to afford the crudeproduct. The crude product was further purified by prep-HPLC to affordcompound 259 as a yellow solid (18 mg, 20%). M.p.: 207˜208° C. LCMS: m/z601.3 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 2.93 (s, 6H), 3.18 (s, 3H),3.82 (s, 3H), 4.96 (s, 2H), 6.78˜6.88 (m, 2H), 7.00 (s, 1H), 7.41˜7.51(m, 3H), 7.57 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 8.14 (s, 1H),8.37 (s, 1H), 8.71 (s, 2H), 8.98 (br, 1H), 10.42 (s, 1H), 11.03 (s, 1H),12.15 (s, 1H).

Example 16: An In Vitro Assay which Determines the Ability of a TestCompound to Inhibit HDAC Enzymatic Activity

HDAC inhibitory activity was assessed using the Biomol Color de Lyssystem (AK-500, Biomol, Plymouth Meeting, Pa.). Briefly, HeLa cellnuclear extracts were used as a source of HDACs. Differentconcentrations of test compounds were serially diluted indimethylsulfoxide (DMSO) and added to HeLa cell nuclear extracts in thepresence of a colorimetric artificial substrate. Final assay conditionscontained 50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl₂.Reactions were carried out at room temperature (25° C.) for 1 hourbefore addition of developer for termination. Relative enzyme activitywas measured in the WALLAC Victor II 1420 microplate reader asfluorescence intensity (excitation: 350-380 nm; emission: 440-460 nm).Data were analyzed using GraphPad Prism (v4.0a) with a sigmoidal doseresponse curve fitting for IC50 calculation.

Example 17: An In Vitro Assay which Determines the Ability of a TestCompound to Inhibit Hedgehog Signalling

Compounds to be tested were dissolved in DMSO to a concentration of 10mM, and stored at −20° C. To activate the Hedgehog pathway in the assaycells, an octylated (lipid-modified) form of the N-terminal fragment ofthe Sonic Hedgehog protein (OCT-SHH) was used. This N-terminal SHHfragment is produced bacterially. See, for example, Taylor F R, et al.,Biochemistry, 2001, 40: 4359-71.

Compounds were tested in the“Gli-Luc” assay below, using the cell line10 Tl/2 (s12), wherein the cells contain a Hedgehog-responsive reporterconstruct utilizing Luciferase as the reporter gene. In this way,Hedgehog pathway signaling activity is measured via the Gli-Lucresponse.

10 Tl/2 (s12) cells were plated in a 96-well micro-titer plate (MTP) at20,000 cells/well in full medium [DMEM with 10% FBS]. Then plates wereplaced in the incubator for incubation overnight (0/N), at 37° C. and 5%CO₂. After 24 h, the medium was replaced with Luciferase-assay medium(DMEM with 0.5% FBS). Test compounds were thawed and diluted in assaymedium at 3:1000 (about 300-fold) resulting in a starting concentrationof about 0.0003 uM to 30 uM. Subsequently, 150 ul of each sample wasadded to the first wells (in triplicate). The MTP samples were thendiluted at 3-fold dilutions to a total of seven wells, ultimatelyresulting in a regiment of seven dilutions in triplicate, for eachcompound. Next, the protein ligand OCT-SHH was diluted inLuciferase-assay medium and added to each well at a final concentrationof 0.3 μg/ml. Plates were then returned to the incubator for furtherincubation O/N, at 37° C. and 5% CO₂. After about 24 h, plates wereremoved from the incubator and the medium was aspirated/discarded.

Wells were washed once with assay buffer [PBS+1 mM Mg²⁺ and 1 mM Ca²⁺].Then 50 μl of assay buffer was added to each well. The Luciferase assayreagent was prepared as described by the vendor (LucLite kit fromPackard), and 50 μl was added to each well. Plates were incubated atroom temperature (RT) for about 30 minutes after which the signals wereread, again at RT, on a Topcount (Packard).

Similar assays were performed using human cell lines (specifically,human embryonic palatal mesenchyme cells, modified with the Gli-Lucconstruct as described above) in a growth medium of MEM/Sodium Pyruvatew/10% FBS, and an assay medium of MEM/Sodium Pyruvate w/0.5% FBS.OCT-SHH was added to reach a final concentration of 1 μg/ml.

Results of the HDAC inhibition and hedgehog inhibition assays describedin Examples 16 and 17, respectively, are set forth in the table below,which indicates the IC50 determined in each assay as follows: I>1000 nM;1000 nM≧II>100 nM; 100 nM≧III>10 nM; 10 nM≧IV>1 nM; 1 nM≧V.

Compound No. HDAC Hh Reporter assay 1 II II 5 II II 7 II I 23 III II 59II III 86 III III 90 III IV 91 III III 111 III II 254 II III 258 III III259 III III 263 III II 265 I 266 II IV SAHA ~40 nM 477 nM Compound A17/24/13.1 nM LBH 589   7 nM

Example 18. An In Vitro Assay which Determines the Ability of a TestCompound to Inhibit Binding of Hedgehog to Smoothened

Smo is transiently overexpressed in 293T cells, the membranes areharvested and a filtration membrane-competition-binding assay isperformed in a 96-well plate with [³H]-Hh-Ag 1.5 added at 2 nM.Membranes are prepared as follows. Briefly, approximately 10⁸ cells aretransfected with pCMV6-XL5 constructs bearing human Smoothened (OriGene)using Fugene 6 (Roche). After 48 hours cells are harvested by scrapingin PBS, centrifuged at 1,000×g for 10 minutes, and gently resuspended inaround 10 ml of a 50 mM Tris pH 7.5, 250 mM sucrose buffer containing anEDTA-free protease inhibitor cocktail (Roche). This cell suspension isthen placed in a nitrogen cavitation device (Parr Instrument Co, Moline,USA) and exposed to nitrogen gas (230 psi) for 10 minutes. Lysed cellsare released from the device and centrifuged at 20,000 rpm in an SS34rotor for 20 minutes at 4° C. Supernatants are discarded and the pelletsare resuspended in 10% sucrose, 50 mM Tris pH 7.5, 5 mM MgCl₂, 1 mM EDTAsolution using three 10-second pulses with a Polytron (Brinkman;Westbury, USA) at a power setting of 12. Using these membranes,filtration binding assays are performed according to standard protocols.Briefly, a test compound is incubated for 1 hour at room temperature inthe following binding buffer (50 mm Tris 7.5, 5 mM MgCl₂, 1 mM EDTA,0.1% BSA) containing cell membrane lysate, [³H]-Hh-Ag 1.5 and proteaseinhibitors. After incubation, the reaction is transferred to a 96-wellfilter plate, vacuum is applied to pull down the reaction buffer, thewells are washed twice and scintillation solution is added. Thereactions are read on a Top Count microplate reader to determine thefraction of [³H]-Hh-Ag 1.5 bound to the smoothened containing membranepreparation.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of Formula (II):

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof; wherein n is 0 or1; Ring A is an aromatic, saturated or partially unsaturated carbocycle;preferably a monocyclic, bicyclic or polycyclic C₃-C₁₂-carbocycle; Q issubstituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl or substituted or unsubstituted saturated or partiallyunsaturated heterocyclyl; G is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or substituted or unsubstitutedsaturated or partially unsaturated heterocyclyl; K is halogen; X isabsent, —O—, —N(R₂)—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R₂)—, —N(R₂)C(O)—, —S(O)₂N(R₂)—, or —N(R₂)S(O)₂—; R₂ is hydrogenor aliphatic; B is a bond or a linker; and D is selected from: (a)

where W is O or S; J is O, NH or NCH₃; and R₃₁ is hydrogen or loweralkyl; (b)

where W is O or S; Y₂ is absent, N, or CH; Z is N or CH; R₃₂ and R₃₄ areindependently hydrogen, hydroxy, aliphatic group, provided that if R₃₂and R₃₄ are both present, one of R₃₂ or R₃₄ must be hydroxy and if Y₂ isabsent, R₃₄ must be hydroxy; and R₃₃ is hydrogen or aliphatic group; (c)

where W is O or S; Y₁ and Z₁ are independently N, C or CH; and (d)

where Z, Y₂, and W are as previously defined; R₁₁ and R₁₂ areindependently selected from hydrogen or aliphatic; R₂₁, R₂₂ and R₂₃ areindependently selected from hydrogen, hydroxy, amino, halogen, alkoxy,alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl, aliphatic,substituted aliphatic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic.
 2. The compoundof claim 1 represented by Formula IV:

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof; wherein Ring A, K,X, B, D, G and Q have the meanings given for these variables in claim 1.3. The compound of claim 1 represented by Formula VI:

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof; wherein K, G, Q, X,B, and D have the meanings given for these variables in claim
 1. 4-7.(canceled)
 8. The compound of claim 1 represented by Formula XII:

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof; wherein X₁-X₅ areeach independently selected from N and CR₃, provided that at least 2 ofX₁-X₅ are CR₃; each R₃ is independently selected from hydrogen, hydroxy,amino, halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic; and Q, D, B and X have the meanings given for thesevariables in claim
 1. 9. The compound of claim 8, wherein Q issubstituted or unsubstituted pyridyl, substituted or unsubstitutedpyrimidyl or substituted or unsubstituted benzimidazolyl.
 10. Thecompound of claim 9, wherein Q is selected from the groups below:

wherein the bond the benzene ring is denoted by

, and the bond to X is denoted by

.
 11. The compound of claim 8, wherein:

is substituted or unsubstituted phenyl, substituted or unsubstitutedpyridyl, or substituted or unsubstituted pyrimidyl.
 12. The compound ofclaim 11, wherein:

is selected from the group consisting of


13. The compound of claim 1, wherein B is a direct bond, straight chainC₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, alkoxyC₁-C₁₀alkylamino, C₁-C₁₀alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀alkenyl,heteroarylC₂-C₁₀alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl,heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀alkynyl,heteroaryloxyC₁-C₁₀alkylamino and heteroaryloxyC₁-C₁₀alkoxy, in each ofwhich one or more methylenes is optionally interrupted or terminated by—O—, —N(R₂)—, —C(O)—, —C(O)N(R₂)—, or —C(O)O—.
 14. The compound of claim1, wherein D is:


15. The compound of claim 14, wherein Y₂ and R₃₂ are absent, Z is N, Wis O, R₃₃ is H and R₃₄ is hydroxy.
 16. (canceled)
 17. The compound ofclaim 1 represented by Formula XIV:

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt or prodrug thereof; wherein M₁ isabsent, O, S, NR₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, heterocyclic, SO, SO₂ or C═O; M₂ is absent, C₁-C₆ alkyl, O,NR₂, heterocyclic, aryl, heteroaryl, or C═O; M₃ is absent, O, NR₂, S,SO, SO₂, CO, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl,heteroaryl, or heterocyclic; M₄ is absent, O, NR₂, heteroaryl,heterocyclic or aryl; M₅ is absent, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₅alkynyl, heteroaryl, heterocyclic or aryl; and G, Q, Z, Y₂, R₂,R₃₂, R₃₃ and R₃₄ are as defined in claim
 1. 18. The compound of claim17, wherein Y₂ and R₃₂ are absent, Z is N, R₃₃ is H and R₃₄ is hydroxy.19. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 20. A method of treating a hedgehogassociated disease or disorder in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of the pharmaceutical composition of claim
 19. 21. The method ofclaim 20, wherein said hedgehog associated disease or disorder is a cellproliferative disorder.
 22. The method of claim 21, wherein said cellproliferative disorder is selected from the group consisting of basalcell carcinoma, neuroectodermal tumors, such as medullablastoma,meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma,squamous lung carcinoma, chondrosarcoma, breast carcinoma,rhabdomyosarcoma, esophageal cancer, stomach cancer, biliary tractcancer, renal carcinoma, leukemia, lymphoma, myeloma and thyroidcarcinoma.
 23. A method for treating a disease or disorder selected frominflammatory conditions, conditions associated with angiogenesis and asa depilatory in a subject, comprising administering to the subject atherapeutically effective amount of the pharmaceutical composition ofclaim
 19. 24. The method of claim 23, wherein the disease or disorder isselected from psoriasis and macular degeneration.
 25. A method oftreating an HDAC-mediated disease comprising administering to a subjectin need thereof a pharmaceutical composition of claim
 19. 26. (canceled)